Amido compounds and their use as pharmaceuticals

ABSTRACT

The present invention relates to inhibitors of 11-β hydroxyl steroid dehydrogenase type 1, antagonists of the mineralocorticoid receptor (MR), and pharmaceutical compositions thereof. The compounds of the invention can be useful in the treatment of various diseases associated with expression or activity of 11-β hydroxyl steroid dehydrogenase type 1 and/or diseases associated with aldosterone excess.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 11/784,450, filedApr. 6, 2007, which is a divisional of U.S. Ser. No. 11/122,309, filedMay 4, 2005, which claims the benefit of U.S. Ser. Nos. 60/569,273,filed May 7, 2004; 60/602,051, filed Aug. 17, 2004; 60/602,791, filedAug. 19, 2004; and 60/638,803, filed Dec. 22, 2004.

FIELD OF THE INVENTION

The present invention relates to modulators of 11-β hydroxyl steroiddehydrogenase type 1 (11βHSD1) and/or mineralocorticoid receptor (MR),compositions thereof and methods of using the same.

BACKGROUND OF THE INVENTION

Glucocorticoids are steroid hormones that regulate fat metabolism,function and distribution. In vertebrates, glucocorticoids also haveprofound and diverse physiological effects on development, neurobiology,inflammation, blood pressure, metabolism and programmed cell death. Inhumans, the primary endogenously-produced glucocorticoid is cortisol.Cortisol is synthesized in the zona fasciculate of the adrenal cortexunder the control of a short-term neuroendocrine feedback circuit calledthe hypothalamic-pituitary-adrenal (HPA) axis. Adrenal production ofcortisol proceeds under the control of adrenocorticotrophic hormone(ACTH), a factor produced and secreted by the anterior pituitary.Production of ACTH in the anterior pituitary is itself highly regulated,driven by corticotropin releasing hormone (CRH) produced by theparaventricular nucleus of the hypothalamus. The HPA axis maintainscirculating cortisol concentrations within restricted limits, withforward drive at the diurnal maximum or during periods of stress, and israpidly attenuated by a negative feedback loop resulting from theability of cortisol to suppress ACTH production in the anteriorpituitary and CRH production in the hypothalamus.

Aldosterone is another hormone produced by the adrenal cortex;aldosterone regulates sodium and potassium homeostasis. Fifty years ago,a role for aldosterone excess in human disease was reported in adescription of the syndrome of primary aldosteronism (Conn, (1955), J.Lab. Clin. Med. 45: 6-17). It is now clear that elevated levels ofaldosterone are associated with deleterious effects on the heart andkidneys, and are a major contributing factor to morbidity and mortalityin both heart failure and hypertension.

Two members of the nuclear hormone receptor superfamily, glucocorticoidreceptor (GR) and mineralocorticoid receptor (MR), mediate cortisolfunction in vivo, while the primary intracellular receptor foraldosterone is the MR. These receptors are also referred to as‘ligand-dependent transcription factors,’ because their functionality isdependent on the receptor being bound to its ligand (for example,cortisol); upon ligand-binding these receptors directly modulatetranscription via DNA-binding zinc finger domains and transcriptionalactivation domains.

Historically, the major determinants of glucocorticoid action wereattributed to three primary factors: 1) circulating levels ofglucocorticoid (driven primarily by the HPA axis), 2) protein binding ofglucocorticoids in circulation, and 3) intracellular receptor densityinside target tissues. Recently, a fourth determinant of glucocorticoidfunction was identified: tissue-specific pre-receptor metabolism byglucocorticoid-activating and -inactivating enzymes. These11-beta-hydroxysteroid dehydrogenase (1′-β-HSD) enzymes act aspre-receptor control enzymes that modulate activation of the GR and MRby regulation of glucocorticoid hormones. To date, two distinct isozymesof 11-beta-HSD have been cloned and characterized: 11βHSD1 (also knownas 11-beta-HSD type 1, 11betaHSD1, HSD11B1, HDL, and HSD11L) and11βHSD2. 11βHSD1 and 11βHSD2 catalyze the interconversion of hormonallyactive cortisol (corticosterone in rodents) and inactive cortisone(11-dehydrocorticosterone in rodents). 11βHSD1 is widely distributed inrat and human tissues; expression of the enzyme and corresponding mRNAhave been detected in lung, testis, and most abundantly in liver andadipose tissue. 11βHSD1 catalyzes both 11-beta-dehydrogenation and thereverse 11-oxoreduction reaction, although 11βHSD1 acts predominantly asa NADPH-dependent oxoreductase in intact cells and tissues, catalyzingthe activation of cortisol from inert cortisone (Low et al. (1994) J.Mol. Endocrin. 13: 167-174) and has been reported to regulateglucocorticoid access to the GR. Conversely, 11βHSD2 expression is foundmainly in mineralocorticoid target tissues such as kidney, placenta,colon and salivary gland, acts as an NAD-dependent dehydrogenasecatalyzing the inactivation of cortisol to cortisone (Albiston et al.(1994) Mol. Cell. Endocrin. 105: R11-R17), and has been found to protectthe MR from glucocorticoid excess, such as high levels ofreceptor-active cortisol (Blum, et al., (2003) Prog. Nucl. Acid Res.Mol. Biol. 75:173-216).

In vitro, the MR binds cortisol and aldosterone with equal affinity. Thetissue specificity of aldosterone activity, however, is conferred by theexpression of 11βHSD2 (Funder et al. (1988), Science 242: 583-585). Theinactivation of cortisol to cortisone by 11βHSD2 at the site of the MRenables aldosterone to bind to this receptor in vivo. The binding ofaldosterone to the MR results in dissociation of the ligand-activated MRfrom a multiprotein complex containing chaperone proteins, translocationof the MR into the nucleus, and its binding to hormone response elementsin regulatory regions of target gene promoters. Within the distalnephron of the kidney, induction of serum and glucocorticoid induciblekinase-1 (sgk-1) expression leads to the absorption of Na⁺ ions andwater through the epithelial sodium channel, as well as potassiumexcretion with subsequent volume expansion and hypertension (Bhargava etal., (2001), Endo 142: 1587-1594).

In humans, elevated aldosterone concentrations are associated withendothelial dysfunction, myocardial infarction, left ventricularatrophy, and death. In attempts to modulate these ill effects, multipleintervention strategies have been adopted to control aldosteroneoveractivity and attenuate the resultant hypertension and its associatedcardiovascular consequences. Inhibition of angiotensin-converting enzyme(ACE) and blockade of the angiotensin type 1 receptor (AT1R) are twostrategies that directly impact the rennin-angiotensin-aldosteronesystem (RAAS). However, although ACE inhibition and AT1R antagonisminitially reduce aldosterone concentrations, circulating concentrationsof this hormone return to baseline levels with chronic therapy (known as‘aldosterone escape’). Importantly, co-administration of the MRantagonist Spironolactone or Eplerenone directly blocks the deleteriouseffects of this escape mechanism and dramatically reduces patientmortality (Pitt et al., New England J. Med. (1999), 341: 709-719; Pittet al., New England J. Med. (2003), 348: 1309-1321). Therefore, MRantagonism may be an important treatment strategy for many patients withhypertension and cardiovascular disease, particularly those hypertensivepatients at risk for target-organ damage.

Mutations in either of the genes encoding the 11-beta-HSD enzymes areassociated with human pathology. For example, 11βHSD2 is expressed inaldosterone-sensitive tissues such as the distal nephron, salivarygland, and colonic mucosa where its cortisol dehydrogenase activityserves to protect the intrinsically non-selective MR from illicitoccupation by cortisol (Edwards et al. (1988) Lancet 2: 986-989).Individuals with mutations in 11βHSD2 are deficient in thiscortisol-inactivation activity and, as a result, present with a syndromeof apparent mineralocorticoid excess (also referred to as ‘SAME’)characterized by hypertension, hypokalemia, and sodium retention (Wilsonet al. (1998) Proc. Natl. Acad. Sci. 95: 10200-10205). Likewise,mutations in 11βHSD1, a primary regulator of tissue-specificglucocorticoid bioavailability, and in the gene encoding a co-localizedNADPH-generating enzyme, hexose 6-phosphate dehydrogenase (H6PD), canresult in cortisone reductase deficiency (CRD), in which activation ofcortisone to cortisol does not occur, resulting inadrenocorticotropin-mediated androgen excess. CRD patients excretevirtually all glucocorticoids as cortisone metabolites(tetrahydrocortisone) with low or absent cortisol metabolites(tetrahydrocortisols). When challenged with oral cortisone, CRD patientsexhibit abnormally low plasma cortisol concentrations. These individualspresent with ACTH-mediated androgen excess (hirsutism, menstrualirregularity, hyperandrogenism), a phenotype resembling polycystic ovarysyndrome (PCOS) (Draper et al. (2003) Nat. Genet. 34: 434-439).

The importance of the HPA axis in controlling glucocorticoid excursionsis evident from the fact that disruption of homeostasis in the HPA axisby either excess or deficient secretion or action results in Cushing'ssyndrome or Addison's disease, respectively (Miller and Chrousos (2001)Endocrinology and Metabolism, eds. Felig and Frohman (McGraw-Hill, NewYork), 4^(th) Ed.: 387-524). Patients with Cushing's syndrome (a raredisease characterized by systemic glucocorticoid excess originating fromthe adrenal or pituitary tumors) or receiving glucocorticoid therapydevelop reversible visceral fat obesity. Interestingly, the phenotype ofCushing's syndrome patients closely resembles that of Reaven's metabolicsyndrome (also known as Syndrome X or insulin resistance syndrome) thesymptoms of which include visceral obesity, glucose intolerance, insulinresistance, hypertension, type 2 diabetes and hyperlipidemia (Reaven(1993) Ann. Rev. Med. 44: 121-131). However, the role of glucocorticoidsin prevalent forms of human obesity has remained obscure becausecirculating glucocorticoid concentrations are not elevated in themajority of metabolic syndrome patients. In fact, glucocorticoid actionon target tissue depends not only on circulating levels but also onintracellular concentration, locally enhanced action of glucocorticoidsin adipose tissue and skeletal muscle has been demonstrated in metabolicsyndrome. Evidence has accumulated that enzyme activity of 11βHSD1,which regenerates active glucocorticoids from inactive forms and plays acentral role in regulating intracellular glucocorticoid concentration,is commonly elevated in fat depots from obese individuals. This suggestsa role for local glucocorticoid reactivation in obesity and metabolicsyndrome.

Given the ability of 11βHSD1 to regenerate cortisol from inertcirculating cortisone, considerable attention has been given to its rolein the amplification of glucocorticoid function. 11βHSD1 is expressed inmany key GR-rich tissues, including tissues of considerable metabolicimportance such as liver, adipose, and skeletal muscle, and, as such,has been postulated to aid in the tissue-specific potentiation ofglucocorticoid-mediated antagonism of insulin function. Considering a)the phenotypic similarity between glucocorticoid excess (Cushing'ssyndrome) and the metabolic syndrome with normal circulatingglucocorticoids in the latter, as well as b) the ability of 11βHSD1 togenerate active cortisol from inactive cortisone in a tissue-specificmanner, it has been suggested that central obesity and the associatedmetabolic complications in syndrome X result from increased activity of11βHSD1 within adipose tissue, resulting in ‘Cushing's disease of theomentum’ (Bujalska et al. (1997) Lancet 349: 1210-1213). Indeed, 11βHSD1has been shown to be upregulated in adipose tissue of obese rodents andhumans (Livingstone et al. (2000) Endocrinology 131: 560-563; Rask etal. (2001) J. Clin. Endocrinol. Metab. 86: 1418-1421; Lindsay et al.(2003) J. Clin. Endocrinol. Metab. 88: 2738-2744; Wake et al. (2003) J.Clin. Endocrinol. Metab. 88: 3983-3988).

Additional support for this notion has come from studies in mousetransgenic models. Adipose-specific overexpression of 11βHSD1 under thecontrol of the aP2 promoter in mouse produces a phenotype remarkablyreminiscent of human metabolic syndrome (Masuzaki et al. (2001) Science294: 2166-2170; Masuzaki et al. (2003) J. Clinical Invest, 112: 83-90).Importantly, this phenotype occurs without an increase in totalcirculating corticosterone, but rather is driven by a local productionof corticosterone within the adipose depots. The increased activity of11βHSD1 in these mice (2-3 fold) is very similar to that observed inhuman obesity (Rask et al. (2001) J. Clin. Endocrinol. Metab. 86:1418-1421). This suggests that local 11βHSD1-mediated conversion ofinert glucocorticoid to active glucocorticoid can have profoundinfluences whole body insulin sensitivity.

Based on this data, it would be predicted that the loss of 11βHSD1 wouldlead to an increase in insulin sensitivity and glucose tolerance due toa tissue-specific deficiency in active glucocorticoid levels. This is,in fact, the case as shown in studies with 11βHSD1-deficient miceproduced by homologous recombination (Kotelevstev et al. (1997) Proc.Natl. Acad. Sci. 94: 14924-14929; Morton et al. (2001) J. Biol. Chem.276: 41293-41300; Morton et al. (2004) Diabetes 53: 931-938). These miceare completely devoid of 11-keto reductase activity, confirming that11βHSD1 encodes the only activity capable of generating activecorticosterone from inert 11-dehydrocorticosterone. 11βHSD1-deficientmice are resistant to diet- and stress-induced hyperglycemia, exhibitattenuated induction of hepatic gluconeogenic enzymes (PEPCK, G6P), showincreased insulin sensitivity within adipose, and have an improved lipidprofile (decreased triglycerides and increased cardio-protective HDL).Additionally, these animals show resistance to high fat diet-inducedobesity. Taken together, these transgenic mouse studies confirm a rolefor local reactivation of glucocorticoids in controlling hepatic andperipheral insulin sensitivity, and suggest that inhibition of 11βHSD1activity may prove beneficial in treating a number ofglucocorticoid-related disorders, including obesity, insulin resistance,hyperglycemia, and hyperlipidemia.

Data in support of this hypothesis has been published. Recently, it wasreported that 11βHSD1 plays a role in the pathogenesis of centralobesity and the appearance of the metabolic syndrome in humans.Increased expression of the 11βHSD1 gene is associated with metabolicabnormalities in obese women and that increased expression of this geneis suspected to contribute to the increased local conversion ofcortisone to cortisol in adipose tissue of obese individuals (Engeli, etal., (2004) Obes. Res. 12: 9-17).

A new class of 11βHSD1 inhibitors, the arylsulfonamidothiazoles, wasshown to improve hepatic insulin sensitivity and reduce blood glucoselevels in hyperglycemic strains of mice (Barf et al. (2002) J. Med.Chem. 45: 3813-3815; Alberts et al. Endocrinology (2003) 144:4755-4762). Furthermore, it was recently reported that selectiveinhibitors of 11βHSD1 can ameliorate severe hyperglycemia in geneticallydiabetic obese mice. Thus, 11βHSD1 is a promising pharmaceutical targetfor the treatment of the Metabolic Syndrome (Masuzaki, et al., (2003)Curr. Drug Targets Immune Endocr. Metabol. Disord. 3: 255-62).

A. Obesity and Metabolic Syndrome

As described above, multiple lines of evidence suggest that inhibitionof 11βHSD1 activity can be effective in combating obesity and/or aspectsof the metabolic syndrome cluster, including glucose intolerance,insulin resistance, hyperglycemia, hypertension, and/or hyperlipidemia.Glucocorticoids are known antagonists of insulin action, and reductionsin local glucocorticoid levels by inhibition of intracellular cortisoneto cortisol conversion should increase hepatic and/or peripheral insulinsensitivity and potentially reduce visceral adiposity. As describedabove, 11βHSD1 knockout mice are resistant to hyperglycemia, exhibitattenuated induction of key hepatic gluconeogenic enzymes, show markedlyincreased insulin sensitivity within adipose, and have an improved lipidprofile. Additionally, these animals show resistance to high fatdiet-induced obesity (Kotelevstev et al. (1997) Proc. Natl. Acad. Sci.94: 14924-14929; Morton et al. (2001) J. Biol. Chem. 276: 41293-41300;Morton et al. (2004) Diabetes 53: 931-938). Thus, inhibition of 11βHSD1is predicted to have multiple beneficial effects in the liver, adipose,and/or skeletal muscle, particularly related to alleviation ofcomponent(s) of the metabolic syndrome and/or obesity.

B. Pancreatic Function

Glucocorticoids are known to inhibit the glucose-stimulated secretion ofinsulin from pancreatic beta-cells (Billaudel and Sutter (1979) Horm.Metab. Res. 11: 555-560). In both Cushing's syndrome and diabetic Zuckerfa/fa rats, glucose-stimulated insulin secretion is markedly reduced(Ogawa et al. (1992) J. Clin. Invest. 90: 497-504). 11βHSD1 mRNA andactivity has been reported in the pancreatic islet cells of ob/ob miceand inhibition of this activity with carbenoxolone, an 11βHSD1inhibitor, improves glucose-stimulated insulin release (Davani et al.(2000) J. Biol. Chem. 275: 34841-34844). Thus, inhibition of 11βHSD1 ispredicted to have beneficial effects on the pancreas, including theenhancement of glucose-stimulated insulin release.

C. Cognition and Dementia

Mild cognitive impairment is a common feature of aging that may beultimately related to the progression of dementia. In both aged animalsand humans, inter-individual differences in general cognitive functionhave been linked to variability in the long-term exposure toglucocorticoids (Lupien et al. (1998) Nat. Neurosci. 1: 69-73). Further,dysregulation of the HPA axis resulting in chronic exposure toglucocorticoid excess in certain brain subregions has been proposed tocontribute to the decline of cognitive function (McEwen and Sapolsky(1995) Curr. Opin. Neurobiol. 5: 205-216). 11βHSD1 is abundant in thebrain, and is expressed in multiple subregions including thehippocampus, frontal cortex, and cerebellum (Sandeep et al. (2004) Proc.Natl. Acad. Sci. Early Edition: 1-6). Treatment of primary hippocampalcells with the 11βHSD1 inhibitor carbenoxolone protects the cells fromglucocorticoid-mediated exacerbation of excitatory amino acidneurotoxicity (Rajan et al. (1996) J. Neurosci. 16: 65-70).Additionally, 11βHSD1-deficient mice are protected fromglucocorticoid-associated hippocampal dysfunction that is associatedwith aging (Yau et al. (2001) Proc. Natl. Acad. Sci. 98: 4716-4721). Intwo randomized, double-blind, placebo-controlled crossover studies,administration of carbenoxolone improved verbal fluency and verbalmemory (Sandeep et al. (2004) Proc. Natl. Acad. Sci. Early Edition:1-6). Thus, inhibition of 11βHSD1 is predicted to reduce exposure toglucocorticoids in the brain and protect against deleteriousglucocorticoid effects on neuronal function, including cognitiveimpairment, dementia, and/or depression.

D. Intra-Ocular Pressure

Glucocorticoids can be used topically and systemically for a wide rangeof conditions in clinical ophthalmology. One particular complicationwith these treatment regimens is corticosteroid-induced glaucoma. Thispathology is characterized by a significant increase in intra-ocularpressure (IOP). In its most advanced and untreated form, IOP can lead topartial visual field loss and eventually blindness. IOP is produced bythe relationship between aqueous humour production and drainage. Aqueoushumour production occurs in the non-pigmented epithelial cells (NPE) andits drainage is through the cells of the trabecular meshwork. 11βHSD1has been localized to NPE cells (Stokes et al. (2000) Invest. Opthalmol.Vis. Sci. 41: 1629-1683; Rauz et al. (2001) Invest. Opthalmol. Vis. Sci.42: 2037-2042) and its function is likely relevant to the amplificationof glucocorticoid activity within these cells. This notion has beenconfirmed by the observation that free cortisol concentration greatlyexceeds that of cortisone in the aqueous humour (14:1 ratio). Thefunctional significance of 11βHSD1 in the eye has been evaluated usingthe inhibitor carbenoxolone in healthy volunteers (Rauz et al. (2001)Invest. Opthalmol. Vis. Sci. 42: 2037-2042). After seven days ofcarbenoxolone treatment, IOP was reduced by 18%. Thus, inhibition of11βHSD1 in the eye is predicted to reduce local glucocorticoidconcentrations and IOP, producing beneficial effects in the managementof glaucoma and other visual disorders.

E. Hypertension

Adipocyte-derived hypertensive substances such as leptin andangiotensinogen have been proposed to be involved in the pathogenesis ofobesity-related hypertension (Matsuzawa et al. (1999) Ann. N.Y. Acad.Sci. 892: 146-154; Wajchenberg (2000) Endocr. Rev. 21: 697-738). Leptin,which is secreted in excess in aP2-11βHSD1 transgenic mice (Masuzaki etal. (2003) J. Clinical Invest. 112: 83-90), can activate varioussympathetic nervous system pathways, including those that regulate bloodpressure (Matsuzawa et al. (1999) Ann. N.Y. Acad. Sci. 892: 146-154).Additionally, the renin-angiotensin system (RAS) has been shown to be amajor determinant of blood pressure (Walker et al. (1979) Hypertension1: 287-291). Angiotensinogen, which is produced in liver and adiposetissue, is the key substrate for renin and drives RAS activation. Plasmaangiotensinogen levels are markedly elevated in aP2-11βHSD1 transgenicmice, as are angiotensin II and aldosterone (Masuzaki et al. (2003) J.Clinical Invest. 112: 83-90). These forces likely drive the elevatedblood pressure observed in aP2-11βHSD1 transgenic mice, Treatment ofthese mice with low doses of an angiotensin II receptor antagonistabolishes this hypertension (Masuzaki et al. (2003) J. Clinical Invest.112: 83-90). This data illustrates the importance of localglucocorticoid reactivation in adipose tissue and liver, and suggeststhat hypertension may be caused or exacerbated by 11βHSD1 activity.Thus, inhibition of 11βHSD1 and reduction in adipose and/or hepaticglucocorticoid levels is predicted to have beneficial effects onhypertension and hypertension-related cardiovascular disorders.

F. Bone Disease

Glucocorticoids can have adverse effects on skeletal tissues. Continuedexposure to even moderate glucocorticoid doses can result inosteoporosis (Cannalis (1996) J. Clin. Endocrinol. Metab. 81: 3441-3447)and increased risk for fractures. Experiments in vitro confirm thedeleterious effects of glucocorticoids on both bone-resorbing cells(also known as osteoclasts) and bone forming cells (osteoblasts).11βHSD1 has been shown to be present in cultures of human primaryosteoblasts as well as cells from adult bone, likely a mixture ofosteoclasts and osteoblasts (Cooper et al. (2000) Bone 27: 375-381), andthe 11βHSD1 inhibitor carbenoxolone has been shown to attenuate thenegative effects of glucocorticoids on bone nodule formation (Bellows etal. (1998) Bone 23: 119-125). Thus, inhibition of 11βHSD1 is predictedto decrease the local glucocorticoid concentration within osteoblastsand osteoclasts, producing beneficial effects in various forms of bonedisease, including osteoporosis.

Small molecule inhibitors of 11βHSD1 are currently being developed totreat or prevent 11βHSD1-related diseases such as those described above.For example, certain amide-based inhibitors are reported in WO2004/089470, WO 2004/089896, WO 2004/056745, and WO 2004/065351.

Antagonists of 11βHSD1 have been evaluated in human clinical trials(Kurukulasuriya, et al., (2003) Curr. Med. Chem. 10: 123-53).

In light of the experimental data indicating a role for 11βHSD1 inglucocorticoid-related disorders, metabolic syndrome, hypertension,obesity, insulin resistance, hyperglycemia, hyperlipidemia, type 2diabetes, androgen excess (hirsutism, menstrual irregularity,hyperandrogenism) and polycystic ovary syndrome (PCOS), therapeuticagents aimed at augmentation or suppression of these metabolic pathways,by modulating glucocorticoid signal transduction at the level of 11βHSD1are desirable.

Furthermore, because the MR binds to aldosterone (its natural ligand)and cortisol with equal affinities, compounds that are designed tointeract with the active site of 11βHSD1 (which binds tocortisone/cortisol) may also interact with the MR and act asantagonists. Because the MR is implicated in heart failure,hypertension, and related pathologies including atherosclerosis,arteriosclerosis, coronary artery disease, thrombosis, angina,peripheral vascular disease, vascular wall damage, and stroke, MRantagonists are desirable and may also be useful in treating complexcardiovascular, renal, and inflammatory pathologies including disordersof lipid metabolism including dyslipidemia or hyperlipoproteinaemia,diabetic dyslipidemia, mixed dyslipidemia, hypercholesterolemia,hypertriglyceridemia, as well as those associated with type 1 diabetes,type 2 diabetes, obesity, metabolic syndrome, and insulin resistance,and general aldosterone-related target-organ damage.

As evidenced herein, there is a continuing need for new and improveddrugs that target 11βHSD1 and/or MR. The compounds, compositions andmethods described herein help meet this and other needs.

SUMMARY OF THE INVENTION

The present invention provides, inter alia, compounds of Formulas I, II,III, IV, Va, Vb, VI, VII, and VIII:

or pharmaceutically acceptable salts or prodrugs thereof, whereinconstituent members are defined herein.

The present invention further provides compositions comprising compoundsof the invention and a pharmaceutically acceptable carrier.

The present invention further provides methods of modulating 11βHSD1 orMR by contacting the 11βHSD1 or MR with a compound of the invention.

The present invention further provides methods of treating diseasesassociated with activity or expression of 11βHSD1 or MR.

DETAILED DESCRIPTION

The present invention provides, inter alia, compounds of Formula I:

or pharmaceutically acceptable salts or prodrugs thereof, wherein:

Cy is aryl, heteroaryl, cycloalkyl or heterocycloalkyl, each optionallysubstituted by 1, 2, 3, 4 or 5-W—X—Y—Z;

R¹ and R² together with the C atom to which they are attached form a 3-,4-, 5-, 6- or 7-membered cycloalkyl group or a 3-, 4-, 5-, 6- or7-membered heterocycloalkyl group, each optionally substituted by 1, 2or 3 R⁵;

R³ and R⁴ together with the N atom to which they are attached form a4-15 membered heterocycloalkyl group optionally substituted by 1, 2, 3,or 4-W′—X′—Y′—Z′;

R⁵ is halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₄ haloalkyl,aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO₂, ORE, SR^(a),C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d),NR^(c)R^(d), NR^(c)C(O)R^(d), NR^(c)C(O)OR^(a), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), or S(O)₂NR^(c)R^(d);

W, W′ and W″ are each, independently, absent, C₁₋₆alkylenyl,C₁₋₆alkenylenyl, C₂₋₆ alkynylenyl, O, S, NR^(e), CO, CS, COO, CONR^(e),OCONR^(e), SO, SO₂, SONR^(e), or NR^(e)CONR^(f), wherein said C₁₋₆alkylenyl, C₂₋₆ alkenylenyl, C₂₋₆ alkynylenyl are each optionallysubstituted by 1, 2 or 3 halo, OH, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, amino,C₁₋₄ alkylamino or C₂₋₈ dialkylamino;

X, X′ and X″ are each, independently, absent, C₁₋₈alkylenyl, C₂₋₈alkenylenyl, C₂₋₅ alkynylenyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl,heterocycloalkylalkyl, arylalkenyl, cycloalkylalkenyl,heteroarylalkenyl, heterocycloalkylalkenyl, arylalkynyl,cycloalkylalkynyl, heteroarylalkynyl, heterocycloalkylalkynyl, each ofwhich is optionally substituted by one or more halo, CN, NO₂, OH, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄ alkylamino or C₂₋₈ dialkylamino;

Y, Y′ and Y″ are each, independently, absent, C₁₋₆ alkylenyl, C₂₋₆alkenylenyl, C₂₋₆ alkynylenyl, O, S, NR^(e), CO, CS, COO, CONR^(e),OCONR^(e), SO, SO₂, SONR^(e), or NR^(e)CONR^(f), wherein said C₁₋₄alkylenyl, C₂₋₆ alkenylenyl, C₂₋₆ alkynylenyl are each optionallysubstituted by 1, 2 or 3 halo, OH, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, amino,C₁₋₄ alkylamino or C₂₋₈dialkylamino;

Z, Z′ and Z″ are each, independently, H, halo, CN, NO₂, OH, C₁₋₄ alkoxy,C₁₋₄ haloalkoxy, amino, C₁₋₄ alkylamino or C₂₋₈ dialkylamino, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl orheterocycloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionallysubstituted by 1, 2 or 3 halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₄ haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO₂,OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(d), NR^(c)C(O)OR^(a),S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b), or S(O)₂NR^(c)R^(d);

wherein two —W—X—Y—Z attached to the same atom optionally form a 3-20membered cycloalkyl or heterocycloalkyl group optionally substituted by1, 2 or 3-W″—X″—Y″—Z″;

wherein two —W′—X′—Y′—Z′ attached to the same atom optionally form a3-20 membered cycloalkyl or heterocycloalkyl group optionallysubstituted by 1, 2 or 3-W″—X″—Y″—Z″;

wherein —W—X—Y—Z is other than H;

wherein —W′—X′—Y′—Z′ is other than H;

wherein W″—X″—Y″—Z″ is other than H;

R^(a) is H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, (C₁₋₆ alkoxy)-C₁₋₆alkyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl;

R^(b) is H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,aryl, cycloalkyl, heteroaryl or heterocycloalkyl;

R^(c) and R^(d) are each, independently, H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, arylalkyl, orcycloalkylalkyl;

or R^(c) and R^(d) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group; and

R^(e) and R^(f) are each, independently, H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, arylalkyl, orcycloalkylalkyl;

or R^(e) and R^(f) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group.

In some embodiments, when R³ and R⁴ together with the N-atom to whichthey are attached form piperidinyl, the piperidinyl is unsubstituted orsubstituted by other than:

wherein:

-   -   V is CH₂CH₂, CH═CH, or CH₂O; and    -   R is H, halo or C₁₋₅ alkyl.

In some embodiments, when R³ and R⁴ together with the N-atom to whichthey are attached form piperazinyl, the Cy is substituted by at leastone —W—X—Y—Z.

In some embodiments, Cy is aryl or heteroaryl, each optionallysubstituted by 1, 2, 3, 4 or 5 —W—X—Y—Z.

In some embodiments, Cy is aryl optionally substituted by 1, 2, 3, 4 or5 —W—X—Y—Z. In some embodiments, Cy is aryl optionally substituted by 1,2 or 3 halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, or C₁₋₄haloalkoxy.

In some embodiments, Cy is phenyl optionally substituted by 1, 2 or 3halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, or C₁₋₄haloalkoxy.

In some embodiments, R¹ and R² together with the C atom to which theyare attached form a 3-, 4-, 5-, 6- or 7-membered cycloalkyl group.

In some embodiments, R¹ and R² together with the C atom to which theyare attached form a cyclopropyl group.

In some embodiments, R³ and R⁴ together with the N atom to which theyare attached form a 4-7 membered heterocycloalkyl group optionallysubstituted by 1, 2, 3, or 4-W′—X′—Y′—Z′.

In some embodiments, R³ and R⁴ together with the N atom to which theyare attached form a piperidinyl or pyrrolidinyl group, each optionallysubstituted by 1, 2, 3, or 4-W′—X′—Y′—Z′.

In some embodiments, R³ and R⁴ together with the N atom to which theyare attached form a piperidinyl or pyrrolidinyl group, each substitutedby 2, 3, or 4-W′—X′—Y′—Z′; wherein two —W′—X′—Y′—Z′ are attached to thesame atom and optionally form a 3-20 membered cycloalkyl orheterocycloalkyl group optionally substituted by 1, 2 or 3-W″—X″—Y″—Z″.

In some embodiments, —W—X—Y—Z is halo, cyano, C₁₋₄ cyanoalkyl, nitro,C₁₋₈ alkyl, C₂₋₈ alkenyl, C₁₋₈ haloalkyl, C₁₋₄ alkylthio, C₁₋₄haloalkylthio, C₁₋₈ alkoxy, C₂₋₈ alkenyloxy, C₁₋₄ haloalkoxy, OH, (C₁₋₄alkoxy)-C₁₋₄ alkyl, amino, C₁₋₄ alkylamino, C₂₋₈ dialkylamino,OC(O)NR^(c)R^(d), NR^(c)C(O)R^(d), NR^(c)C(O)OR^(a), NR^(c)S(O)₂R^(d),C(O)OR^(a), C(O)R^(a), C(O)NR^(a)NR^(c)R^(d), S(O)₂R^(d), SR^(d),C(O)NR^(c)R^(d), C(S)NR^(c)R^(d), aryloxy, heteroaryloxy, cycloalkyloxy,cycloalkenyloxy, heterocycloalkyloxy, arylalkyloxy, heteroarylalkyloxy,cycloalkylalkyloxy, heterocycloalkylalkyloxy, heteroaryloxyalkyl,aryloxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl,arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl,heteroarylalkynyl, cycloalkylalkyl, or heterocycloalkylalkyl;

wherein each of said C₁₋₈ alkyl, C₂₋₈ alkenyl, C₁₋₈haloalkyl, C₁₋₄alkylthio, C₁₋₄haloalkylthio, C₁₋₈ alkoxy, aryloxy, heteroaryloxy,arylalkyloxy, heteroarylalkyloxy, heteroaryloxyalkyl, aryloxy,heteroaryloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy,arylalkyloxy, heteroarylalkyloxy, cycloalkylalkyloxy,heterocycloalkylalkyloxy, heteroaryloxyalkyl, aryloxyalkyl, aryl,heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, arylalkenyl,arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl,cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted by1, 2, or 3 halo, cyano, nitro, hydroxyl-(C₁₋₆alkyl), aminoalkyl,dialkylaminoalkyl, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄cyanoalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, OH, OR^(a), (C₁₋₄ alkoxy)-C₁₋₄ alkyl, amino,C₁₋₄ alkylamino, C₂₋₈ dialkylamino, C(O)NR^(c)R^(d), C(O)OR^(a),C(O)R^(a), (cycloalkylalkyl)-C(O)—, NR^(c)C(O)R^(d), NR^(c)C(O)OR^(a),NR^(c)S(O)₂R^(d), C(S)NR^(c)R^(d), S(O)₂R^(d), SR^(d), (C₁₋₄alkyl)sulfonyl, arylsulfonyl, aryl optionally substituted by halo,heteroaryl, cycloalkylalkyl, cycloalkyl, or heterocycloalkyl.

In some embodiments, —W—X—Y—Z is halo, cyano, C₁₋₄ cyanoalkyl, nitro,C₁₋₈ alkyl, C₁₋₅ alkenyl, C₁₋₈haloalkyl, C₁₋₁₀alkoxy, C₁₋₄haloalkoxy,OH, C₁₋₈ alkoxyalkyl, amino, C₁₋₄alkylamino, C₂₋₈ dialkylamino,OC(O)NR^(c)R^(d), NR^(c)C(O)R^(d), NR^(c)C(O)OR^(a), aryloxy,heteroaryloxy, arylalkyloxy, heteroarylalkyloxy, heteroaryloxyalkyl,aryloxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl,arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl,heteroarylalkynyl, cycloalkylalkyl, or heterocycloalkylalkyl;

wherein each of said C₁₋₈ alkyl, C₁₋₈ alkenyl, C₁₋₈ haloalkyl, C₁₋₈alkoxy, aryloxy, heteroaryloxy, arylalkyloxy, heteroarylalkyloxy,heteroaryloxyalkyl, aryloxyalkyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl,heteroarylalkenyl heteroarylalkynyl, cycloalkylalkyl, orheterocycloalkylalkyl is optionally substituted by 1, 2, or 3 halo,cyano, nitro, hydroxyl-(C₁₋₆ alkyl), aminoalkyl, dialkylaminoalkyl, C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, OH, C₁₋₈alkoxyalkyl, amino, C₁₋₄ alkylamino, C₂₋₈ dialkylamino, C(O)NR^(c)R^(d),C(O)OR^(a), NR^(c)C(O)R^(d), NR^(c)S(O)₂R^(d), (C₁₋₄ alkyl)sulfonyl,arylsulfonyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl.

12. The compound of claim 1 wherein —W—X—Y—Z is halo, cyano, C₁₋₄cyanoalkyl, nitro, C₁₋₄ nitroalkyl, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, OH, (C₁₋₄ alkoxy)-C₁₋₄ alkyl, amino, C₁₋₄alkylamino, C₂₋₈ dialkylamino, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, orheterocycloalkylalkyl.

In some embodiments, —W—X—Y—Z is halo, C₁₋₄ alkyl, or C₁₋₄ alkoxy.

In some embodiments, —W′—X′—Y′—Z′ is halo, OH, cyano, CHO, COOH,C(O)O—(C₁₋₄ alkyl), C(O)—(C₁₋₄ alkyl), SO₂—(C₁₋₄ alkyl), C₁₋₄ alkyl,C₁₋₄ alkoxy or -L-R⁷, wherein said C₁₋₄ alkyl or C₁₋₄ alkoxy isoptionally substituted by one or more halo, OH, COOH or C(O)O—(C₁₋₄alkyl);

In some embodiments, —W′—X′—Y′—Z′ is halo; C₁₋₄ alkyl; C₁₋₄ haloalkyl;OH; C₁₋₄ alkoxy; C₁₋₄ haloalkoxy; hydroxyalkyl; alkoxyalkyl; aryl;heteroaryl; aryl substituted by halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, aryl,heteroaryl, or aryloxy; or heteroaryl substituted by halo, C₁₋₄ alkyl,C₁₋₄ alkoxy, aryl, or heteroaryl.

In some embodiments, —W′—X′—Y′—Z′ are attached to the same atom andoptionally form a 3-20 membered cycloalkyl or heterocycloalkyl groupoptionally substituted by 1, 2 or 3 —W″—X″—Y″—Z″.

In some embodiments, —W″—X″—Y″—Z″ is halo, cyano, C₁₋₄ cyanoalkyl,nitro, C₁₋₄ nitroalkyl, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, OH, (C₁₋₄ alkoxy)-C₁₋₄ alkyl, amino, C₁₋₄ alkylamino, C₁₋₈dialkylamino, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl.

In some embodiments:

—W′—X′—Y′—Z′ is halo, OH, cyano, CHO, COOH, C(O)O—(C₁₋₄ alkyl), C(O)₄C₁₋₄ SO₂—(C₁₋₄ alkyl), C₁₋₄ alkyl, C₁₋₄ alkoxy or wherein said C₁₋₄alkyl or C₁₋₄ alkoxy is optionally substituted by one or more halo, OH,COOH or C(O)O—(C₁₋₄ alkyl);

L is absent, O, CH₂, NHSO₂, N[C(O)—(C₁₋₄ alkyl)]; and

R⁷ is aryl or heteroaryl, each is optionally substituted by 1, 2, or 3halo, OH, cyano, CHO, COOH, C(O)O—(C₁₋₄ alkyl), C(O)—(C₁₋₄ alkyl),SO₂—(C₁₋₄ alkyl), SO₂—NH(C₁₋₄ alkyl), C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄haloalkyl, C₁₋₄ hydroxyalkyl, aryl, heteroaryl or aryloxy.

In some embodiments, the compounds of the invention have Formula II:

including pharmaceutically acceptable salts or prodrugs thereof, whereinconstituent variables are defined herein above, and q is 0, 1, 2, 3 or4.

In some embodiments, Cy is aryl or heteroaryl, each optionallysubstituted by 1, 2, 3, 4 or 5 —W—X—Y—Z.

In some embodiments, q is 1, 2, 3 or 4.

In some embodiments, q is 2, 3 or 4.

In some embodiments, two —W′—X′—Y′—Z′ attached to the same atom form a3-20 membered cycloalkyl or heterocycloalkyl group optionallysubstituted by 1, 2 or 3 —W″—X″—Y″—Z″.

The present invention further provides compounds of Formula III:

or pharmaceutically acceptable salts or prodrugs thereof, whereinconstituent variables are defined hereinabove; and

r is 0, 1, 2, 3 or 4.

In some embodiments, when U is CH₂, then —W′—X′—Y′—Z′ forms a groupother than:

wherein:

V is CH₂CH₂, CH═CH, or CH₂O; and

R is H, halo or C₁₋₅ alkyl.

In some embodiments, when U is NH, Cy is substituted by at least one—W—X—Y—Z.

In some embodiments, r is 1, 2, 3 or 4.

In some embodiments, r is 2, 3 or 4.

In some embodiments, U is CH₂.

In some embodiments, two —W′—X′—Y′—Z′ attached to the same atom form a3-20 membered cycloalkyl or heterocycloalkyl group optionallysubstituted by 1, 2 or 3 —W″—X″—Y″—Z″.

The present invention further provides compounds of Formula IV:

or pharmaceutically acceptable salts or prodrugs thereof, whereinconstituent variables are defined hereinabove:

G¹ and G² together with the carbon atom to which they are attached forma 3-20 membered cycloalkyl or heterocycloalkyl group optionalsubstituted by 1, 2 or 3 —W″—X″—Y″—Z″; and

v is 0, 1 or 2.

In some embodiments, v is 0.

In some embodiments, v is 1.

In some embodiments, G¹ and G² together with the carbon atom to whichthey are attached form a 9-14 membered cycloalkyl or heterocycloalkylgroup optional substituted by 1, 2 or 3 —W″

In some embodiments, —W″—X″—Y″—Z″ is halo, cyano, cyanoalkyl, nitro,C₁₋₄ nitroalkyl, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄haloalkoxy, OH, (C₁₋₄ alkoxy)-C₁₋₄ alkyl, amino, C₁₋₄ alkylamino, C₂₋₈dialkylamino, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl.

The present invention further provides compounds of Formula Va or Vb:

or pharmaceutically acceptable salts or prodrugs thereof, whereinconstituent variables are defined herein above:

ring B is a fused 5 or 6-membered aryl or heteroaryl group;

Q¹ is O, S, NH, CH₂, CO, CS, SO, SO₂, OCH₂, SCH₂, NHCH₂, CH₂CH₂, CH═CH,COCH₂, CONH, COO, SOCH₂, SONH, SO₂CH₂, or SO₂NH;

Q² is O, S, NH, CH₂, CO, CS, SO, SO₂, OCH₂, SCH₂, NHCH₂, CH₂CH₂, CH═CH,COCH₂, CONH, COO, SOCH₂, SONH, SO₂CH₂, or SO₂NH;

q is 0 or 1;

v is 0, 1 or 2;

r is 0, 1 or 2;

s is 0, 1 or 2; and

the sum of r and s is 0, 1 or 2.

In some embodiments, Q¹ and Q² are selected to form a 1-, 2-, or 3-atomspacer. In further embodiments, Q¹ and Q² when bonded together form aspacer group having other than an O—O or O—S ring-forming bond.

In some embodiments, Q¹ is O, S, NH, CH₂ or CO, wherein each of said NHand CH₂ is optionally substituted by —W″—X″—Y″—Z″.

In some embodiments, Q¹ is O, NH, CH₂ or CO, wherein each of said NH andCH₂ is optionally substituted by —W″—X″—Y″—Z″.

In some embodiments, Q² is O, S, NH, CH₂, CO, or SO₂, wherein each ofsaid NH and CH₂ is optionally substituted by —W″—X″—Y″—Z″.

In some embodiments, one of Q¹ and Q² is O and the other is CO or CONH,wherein said CONH is optionally substituted by —W″—X″—Y″—Z″.

In some embodiments, one of Q¹ and Q² is CO and the other is O, NH, orCH₂, and wherein each of said NH and CH₂ is optionally substituted by—W″—X″—Y″—Z″.

In some embodiments, one of Q¹ and Q² is CH₂ and the other is O, S, NH,or CH₂, and wherein each of said NH and CH₂ is optionally substituted by—W″—X″—Y″—Z″.

In some embodiments, one of Q¹ and Q² is CO.

In some embodiments, the compound has Formula Va wherein one of Q¹ andQ² is CO and the other is O, NH, or CH₂, and wherein each of said NH andCH₂ is optionally substituted by —W″

In some embodiments, the compound has Formula Va wherein one of Q¹ andQ² is CH₂ and the other is O, S, NH, or CH₂, and wherein each of said NHand CH₂ is optionally substituted by —W″

In some embodiments, the compound has Formula Vb wherein one of Q¹ andQ² is CO.

In some embodiments, the compound has Formula Va.

In some embodiments, the compound has Formula Vb.

In some embodiments, ring B is phenyl or pyridyl.

In some embodiments, ring B is phenyl,

In some embodiments, r is 0.

In some embodiments, r is 0 or 1.

In some embodiments, s is 0 or 1.

The present invention further provides compounds of Formula VI:

pharmaceutically acceptable salt forms and prodrugs thereof, whereinconstituent variables are defined hereinabove, and Q³ and Q⁴ are each,independently, CH or N.

In some embodiments, Q³ is CH optionally substituted by —W″—X″—Y″—Z″.

In some embodiments, Q³ is N.

In some embodiments, Q⁴ is CH optionally substituted by —W″—X″—Y″—Z″.

In some embodiments, Q⁴ is N.

In some embodiments, Q³ is CH and Q⁴ is CH, each optionally substitutedby —W″—X″—Y″—Z″.

In some embodiments, Q³ is CH and Q⁴ is N, wherein said Q³ is optionallysubstituted by

In some embodiments, Q³ is N and Q⁴ is CH optionally substituted by—W″—X″—Y″—Z″.

In some embodiments, Q¹ is O, NH, CH₂ or CO, wherein each of said NH andCH₂ is optionally substituted by —W″—X″—Y″—Z″.

In some embodiments, Q² is O, S, NH, CH₂, CO, or SO₂, wherein each ofsaid NH and CH₂ is optionally substituted by —W″—X″—Y″—Z″.

In some embodiments, one of Q¹ and Q² is CO and the other is O, NH, orCH₂, wherein each of said NH and CH₂ is optionally substituted by—W″—X″—Y″—Z″.

In some embodiments, one of Q¹ and Q² is CH₂ and the other is O, S, NH,or CH₂, wherein each of said NH and CH₂ is optionally substituted by—W″—X″—Y″—Z″.

In some embodiments, one of Q¹ and Q² is O and the other is CO or CONH,wherein said CONH is optionally substituted by —W″—X″—Y″—Z″.

In some embodiments, r is 0 or 1.

In some embodiments, s is 0 or 1.

The present invention further provides compounds of Formula VII:

pharmaceutically acceptable salts and prodrugs thereof, whereinconstituent variables are defined hereinabove.

The present invention further provides compounds of having Formula VIII:

pharmaceutically acceptable salts and prodrugs thereof, whereinconstituent variables are defined hereinabove.

In some embodiments, Q¹ is O, NH, CH₂ or CO, wherein each of said NH andCH₂ is optionally substituted by —W″—X″—Y″—Z″.

In some embodiments, Q² is O, S, NH, CH₂, CO, or SO₂, wherein each ofsaid NH and CH₂ is optionally substituted by —W″—X″—Y″—Z″.

In some embodiments, one of Q¹ and Q² is CO and the other is O, NH, orCH₂, wherein each of said NH and CH₂ is optionally substituted by—W″—X″—Y″—Z″

In some embodiments, one of Q¹ and Q² is CH₂ and the other is O, S, NH,or CH₂, wherein each of said NH and CH₂ is optionally substituted by—W″—X″—Y″—Z″.

In some embodiments, one of Q¹ and Q² is O and the other is CO or CONH,wherein said CONH is optionally substituted by —W″—X″—Y″—Z″.

In some embodiments, Q³ is CH optionally substituted by —W″—X″—Y″—Z″.

In some embodiments, Q³ is N.

In some embodiments, Q⁴ is CH optionally substituted by —W″—X″—Y″—Z″.

In some embodiments, Q⁴ is N.

In some embodiments, r is 0 or 1.

In some embodiments, s is 0 or 1.

At various places in the present specification, substituents ofcompounds of the invention are disclosed in groups or in ranges. It isspecifically intended that the invention include each and everyindividual subcombination of the members of such groups and ranges. Forexample, the term “C₁₋₆ alkyl” is specifically intended to individuallydisclose methyl, ethyl, C₃ alkyl, C₄ alkyl, C₅ alkyl, and C₆ alkyl.

For compounds of the invention in which a variable appears more thanonce, each variable can be a different moiety selected from the Markushgroup defining the variable. For example, where a structure is describedhaving two R groups that are simultaneously present on the samecompound; the two R groups can represent different moieties selectedfrom the Markush group defined for R. In another example, when anoptionally multiple substituent is designated in the form:

then it is understood that substituent R can occur s number of times onthe ring, and R can be a different moiety at each occurrence. Further,in the above example, should the variable Q be defined to includehydrogens, such as when Q is said to be CH₂, NH, etc., any floatingsubstituent such as R in the above example, can replace a hydrogen ofthe Q variable as well as a hydrogen in any other non-variable componentof the ring.

It is further intended that the compounds of the invention are stable.As used herein “stable” refers to a compound that is sufficiently robustto survive isolation to a useful degree of purity from a reactionmixture, and preferably capable of formulation into an efficacioustherapeutic agent.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment. Conversely,various features of the invention which are, for brevity, described inthe context of a single embodiment, can also be provided separately orin any suitable subcombination.

As used herein, the term “alkyl” is meant to refer to a saturatedhydrocarbon group which is straight-chained or branched. Example alkylgroups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl andisopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g.,n-pentyl, isopentyl, neopentyl), and the like. An alkyl group cancontain from 1 to about 20, from 2 to about 20, from 1 to about 10, from1 to about 8, from 1 to about 6, from 1 to about 4, or from Ito about 3carbon atoms. The term “alkylenyl” refers to a divalent alkyl linkinggroup.

As used herein, “alkenyl” refers to an alkyl group having one or moredouble carbon-carbon bonds. Example alkenyl groups include ethenyl,propenyl, cyclohexenyl, and the like. The term “alkenylenyl” refers to adivalent linking alkenyl group. An example C₁ alkenylenyl is —CH═.

As used herein, “alkynyl” refers to an alkyl group having one or moretriple carbon-carbon bonds. Example alkynyl groups include ethynyl,propynyl, and the like. The term “alkynylenyl” refers to a divalentlinking alkynyl group.

As used herein, “haloalkyl” refers to an alkyl group having one or morehalogen substituents. Example haloalkyl groups include CF₃, C₂F₅, CHF₂,CCl₃, CHCl₂, C₂Cl₅, and the like.

As used herein, “aryl” refers to monocyclic or polycyclic (e.g., having2, 3 or 4 fused rings) aromatic hydrocarbons such as, for example,phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and thelike. In some embodiments, aryl groups have from 6 to about 20 carbonatoms.

As used herein, “cycloalkyl” refers to non-aromatic cyclic hydrocarbonsincluding cyclized alkyl, alkenyl, and alkynyl groups. Cycloalkyl groupscan include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings)ring systems as well as 2-ring, 3-ring, 4-ring spiro system (e.g.,having 8 to 20 ring-forming atoms). Example cycloalkyl groups includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl,norbornyl, norpinyl, norcarnyl, adamantyl, and the like. Also includedin the definition of cycloalkyl are moieties that have one or morearomatic rings fused (i.e., having a bond in common with) to thecycloalkyl ring, for example, benzo, pyrido or thieno derivatives ofpentane, pentene, hexane, and the like. Carbon atoms of the cycloalkylgroup can be optionally oxidized, e.g. bear an oxo or sulfido group toform CO or CS.

As used herein, “heteroaryl” groups refer to an aromatic heterocyclehaving at least one heteroatom ring member such as sulfur, oxygen, ornitrogen. Heteroaryl groups include monocyclic and polycyclic (e.g.,having 2, 3 or 4 fused rings) systems. Examples of heteroaryl groupsinclude without limitation, pyridyl, N-oxopyridyl, pyrimidinyl,pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl,thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl,benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl,tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl,purinyl, carbazolyl, benzimidazolyl, indolinyl, and the like. In someembodiments, the heteroaryl group has from 1 to about 20 carbon atoms,and in further embodiments from about 3 to about 20 carbon atoms. Insome embodiments, the heteroaryl group contains 3 to about 14, 3 toabout 7, or 5 to 6 ring-forming atoms. In some embodiments, theheteroaryl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms.

As used herein, “heterocycloalkyl” refers to non-aromatic heterocyclesincluding cyclized alkyl, alkenyl, and alkynyl groups where one or moreof the ring-forming carbon atoms is replaced by a heteroatom such as anO, N, or S atom. Also included in the definition of heterocycloalkyl aremoieties that have one or more aromatic rings fused (i.e., having a bondin common with) to the nonaromatic heterocyclic ring, for examplephthalimidyl, naphthalimidyl, and benzo derivatives of heterocycles suchas indolene and isoindolene groups. Heterocycloalkyl groups can be mono-or polycyclic (e.g., having 2, 3, 4 or more fused rings or having a2-ring, 3-ring, 4-ring spiro system (e.g., having 8 to 20 ring-formingatoms)). Heteroatoms or carbon atoms of the heterocycloalkyl group canbe optionally oxidized, e.g., bearing one or two oxo or sulfido groupsto form SO, SO₂, CO, NO, etc. In some embodiments, the heterocycloalkylgroup has from 1 to about 20 carbon atoms, and in further embodimentsfrom about 3 to about 20 carbon atoms. In some embodiments, theheterocycloalkyl group contains 3 to about 14, 3 to about 7, or 5 to 6ring-forming atoms. In some embodiments, the heterocycloalkyl group has1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. In some embodiments,the heterocycloalkyl group contains 0 to 3 double bonds. In someembodiments, the heterocycloalkyl group contains 0 to 2 triple bonds.Example “heterocycloalkyl” groups include morpholino, thiomorpholino,piperazinyl, tetrahydrofuranyl, tetrahydrothienyl,2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-1,4-dioxane, piperidinyl,pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl,oxazolidinyl, thiazolidinyl, imidazolidinyl, as well as radicals of3H-isobenzofuran-1-one, 1,3-dihydro-isobenzofuran,2,3-dihydro-benzo[d]isothiazole 1,1-dioxide, and the like.

As used herein, “halo” or “halogen” includes fluoro, chloro, bromo, andiodo.

As used herein, “alkoxy” refers to an —O-alkyl group. Example alkoxygroups include methoxy, ethoxy, propoxy (e.g., n-propoxy andisopropoxy), t-butoxy, and the like.

As used here, “haloalkoxy” refers to an —O-haloalkyl group. An examplehaloalkoxy group is OCF₃.

As used herein, “arylalkyl” refers to alkyl substituted by aryl and“cycloalkylalkyl” refers to alkyl substituted by cycloalkyl. An examplearylalkyl group is benzyl.

As used herein, “amino” refers to NH₂.

As used herein, “alkylamino” refers to an amino group substituted by analkyl group.

As used herein, “dialkylamino” refers to an amino group substituted bytwo alkyl groups.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent invention that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically active starting materialsare known in the art, such as by resolution of racemic mixtures or bystereoselective synthesis. Many geometric isomers of olefins, C═N doublebonds, and the like can also be present in the compounds describedherein, and all such stable isomers are contemplated in the presentinvention. Cis and trans geometric isomers of the compounds of thepresent invention are described and may be isolated as a mixture ofisomers or as separated isomeric forms.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. An example method includes fractionalrecrystallization using a “chiral resolving acid” which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid orthe various optically active camphorsulfonic acids such asβ-camphorsulfonic acid. Other resolving agents suitable for fractionalcrystallization methods include stereoisomerically pure forms ofα-methylbenzylamine (e.g., S and R forms, or diastereomerically pureforms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

Compounds of the invention also include tautomeric forms, such asketo-enol tautomers.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgement, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. As used herein, “pharmaceuticallyacceptable salts” refers to derivatives of the disclosed compoundswherein the parent compound is modified by converting an existing acidor base moiety to its salt form. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts of the present invention include the conventionalnon-toxic salts or the quaternary ammonium salts of the parent compoundformed, for example, from non-toxic inorganic or organic acids. Thepharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), eachof which is incorporated herein by reference in its entirety.

The present invention also includes prodrugs of the compounds describedherein. As used herein, “prodrugs” refer to any covalently bondedcarriers which release the active parent drug when administered to amammalian subject. Prodrugs can be prepared by modifying functionalgroups present in the compounds in such a way that the modifications arecleaved, either in routine manipulation or in vivo, to the parentcompounds. Prodrugs include compounds wherein hydroxyl, amino,sulfhydryl, or carboxyl groups are bonded to any group that, whenadministered to a mammalian subject, cleaves to form a free hydroxyl,amino, sulfhydryl, or carboxyl group respectively. Examples of prodrugsinclude, but are not limited to, acetate, formate and benzoatederivatives of alcohol and amine functional groups in the compounds ofthe invention. Preparation and use of prodrugs is discussed in T.Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 ofthe A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987, both of which are hereby incorporated by referencein their entirety.

Synthesis

The novel compounds of the present invention can be prepared in avariety of ways known to one skilled in the art of organic synthesis.The compounds of the present invention can be synthesized using themethods as hereinafter described below, together with synthetic methodsknown in the art of synthetic organic chemistry or variations thereon asappreciated by those skilled in the art.

The compounds of this invention can be prepared from readily availablestarting materials using the following general methods and procedures.It will be appreciated that where typical or preferred processconditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given; other processconditions can also be used unless otherwise stated. Optimum reactionconditions may vary with the particular reactants or solvent used, butsuch conditions can be determined by one skilled in the art by routineoptimization procedures.

The processes described herein can be monitored according to anysuitable method known in the art. For example, product formation can bemonitored by spectroscopic means, such as nuclear magnetic resonancespectroscopy (e.g., ¹H or ¹³C) infrared spectroscopy, spectrophotometry(e.g., UV-visible), or mass spectrometry, or by chromatography such ashigh performance liquid chromatography (HPLC) or thin layerchromatography.

Preparation of Compounds can Involve the Protection and Deprotection ofVarious Chemical groups. The need for protection and deprotection, andthe selection of appropriate protecting groups can be readily determinedby one skilled in the art. The chemistry of protecting groups can befound, for example, in Greene, et al., Protective Groups in OrganicSynthesis, 2d. Ed., Wiley & Sons, 1991, which is incorporated herein byreference in its entirety.

The reactions of the processes described herein can be carried out insuitable solvents which can be readily selected by one of skill in theart of organic synthesis. Suitable solvents can be substantiallynonreactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,i.e., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent invention that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically active starting materialsare known in the art, such as by resolution of racemic mixtures or bystereoselective synthesis.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. An example method includes fractionalrecrystallization using a “chiral resolving acid” which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid orthe various optically active camphorsulfonic acids. Resolution ofracemic mixtures can also be carried out by elution on a column packedwith an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

The compounds of the invention can be prepared, for example, using thereaction pathways and techniques as described below.

A series of cycloalkylcarboxmides of formula 2 can be prepared by themethod outlined in Scheme 1. The carboxylic acids 1 can be coupled to anamine using coupling reagents such as BOP to provide the desired product2.

A series of cycloalkylcarboxylic acids formula 3 can be prepared by themethod outlined in Scheme 2. Mono-alkylation of alpha-substituted methyl4 with an alkylenedihalide such as ethylene bromide, 1,3-dibromopropane,and 1,4-dibromobutane provides mono-alkylated product 5, followed bytreatment with either 1) sodium hydride in DMSO or DMF or 2) LDA in THFprovides the cycloalkylcarboxylic acid esters 6. Hydrolysis of 6 givesthe corresponding acid 3.

Alternatively, a series of cycloalkylcarboxylic acids of formula 7 canbe prepared from the corresponding nitrile as exemplified in Scheme 3.Alpha-substituted acetonitrile 8 can be treated with potassium hydroxideand alkylenedihalides such as 1,3-dibromopropane to provide substitutedcycloalkylcarbonitriles 10, which is then followed by hydrolysis toafford the desired cycloalkylcarboxylic acid 7.

A series of 3-substituted pyrrolidines 10 and 11 can be prepared by themethod outlined in Scheme 4 (R″ can be, for example, alkyl orcycloalkyl). Compound 12 can be treated with organolithium or Grignardreagent to provide alcohol 13. The Boc protecting group of 13 can beremoved by treating with TFA to give 3-substituted pyrrolidine 10.Alternatively, 13 can be treated with HCl to provide the alkene 14,followed by the dehydrogenation to give 3-substituted pyrrolidine

A series of 3-substituted pyrrolidines 11a can be prepared by the methodoutlined in Scheme 5 (Ar can be, for example, aryl or heteroaryl).Palladium catalyzed Heck coupling reaction of alkene 15 witharylbromides or heteroarylbromides, followed by hydrogenation directlyprovides the desired 3-substituted pyrrolidine 11a (Ho, C. et alTetrahedron Lett. 2004, 45, 4113).

A series of 3-hydroxyl, 4-substituted pyrrolidines 16 can be prepared bythe method outlined in Scheme 6 (Ar can be, for example, aryl orheteroaryl; X can be halo). Alkene 15 can be reacted with MCPBA toprovide the epoxide 17, followed by treatment with organolithium andLewis acid, such as Al(Me)₃, to give the desired 3-hydroxyl,4-substituted pyrrolidine 16.

A series of di-substituted pyrrolidines or piperidines 18 are preparedby the method outlined in Scheme 7 (Ar is, for example, aryl orheteroaryl; n is 1 or 2 and m is 1 or 2). Ketone 19 can be treated witha Wittig reagent to provide vinyl compound 20, followed by reacting withAr₂CuLi to provide the addition product 21. The Cbz protecting group of21 can be removed by hydrogenation to provide the desired disubstitutedpyrrolidine or disubstituted piperidine 18.

A series of compounds 22 can be prepared by the method outlined inScheme 8 (Ar is, for example, aryl or heteroaryl; and NR^(i)R^(ii) is,for example, amine, alkylamine, dialkylamine and derivatives thereof).The carboxylicacid 1 can be coupled with an amino alcohol using BOP orother amide bond formation reagents to provide the coupled product 23.The hydroxyl group of the coupled product 23 can be alkylated with2-bromoacetate to give compound 24 and the tert-butyl group of 24 can beremoved by treatment with TFA, followed by a standard coupling reactionwith a variety amines to give compounds 22.

According to Scheme 9 (Ar is, for example, aryl or heteroaryl), thehydroxyl group of 23 can be alkylated with protected 2-amino ethylbromide to give compound 25. The protecting group of 25 can be removedby TFA. The resulting free amino group of compound 26 can be convertedinto a variety analogs 27 by methods known to those skilled in the art.

A series of compounds 28 can be prepared by the method outlined inScheme 10. Compound 29 can be treated with alkyldihalides such as1,2-dibromoethane or a similar reagent to give the desired cycloalkylproduct 30. Both benzyl (Bn) groups of 30 can be removed byhydrogenation to give the deprotected compound 31. Treatment with cyclicamines NHR³R⁴ can provide amides of formula 32. The free hydroxyl groupof 32 can be converted to a variety ether analogs 28 by methods known tothose skilled in the art such as by substitution reactions employingbase (e.g., NaH) and electrophile (RX where R is alkyl, cycloalkyl, etc.and X is halo or other leaving group).

A series of compounds 33 can be prepared by the method outlined inScheme 11 (Ar is, for example, aryl or heteroaryl or derivativesthereof). The free hydroxyl group of 32 can be protected to yield 34,which then can undergo Pd catalyzed coupling to provide compounds 33.

A series of compounds 35 can be prepared by the method outlined inScheme 12 (Ar can be, for example, aryl or heteroaryl or derivativesthereof). The free phenol group of 32 can be coupled with ArB(OH)₂directly to provide the aryl or heteroaryl ether coupling product 35(Bolm, C. et al. J. Org. Chem. 2005, 70, 2346).

A series of 4-heterocyclo-substituted ether compounds 36 and 37 can beprepared by the method outlined in Scheme 13 (G is, e.g., O, NBoc, NMe,etc.). The free phenol of 32 can be treated with a variety ofheterocycloalkylalkyl triflates or heterocycloalkylalkyl halides toprovide 4-heterocycloalkyl-substituted ether compounds 36 and 37,respectively.

Spiro-pyrrolidines 56 can be prepared according to Scheme 14. Halogenmetal exchange between aryl iodide 54 and isopropylmagnesium bromidefollowed by reaction with N-Boc-3-oxo-pyrrolidine provides spiro-lactone55 which upon acidic cleavage of the Boc group yields the desiredpyrrolidine 56.

Spiro-pyrrolidines 59 can be prepared according to Scheme 15.Ortho-lithiation of carboxylic acid 57, followed by reaction of theresulting organolithium with N-Boc-3-oxo-pyrrolidine yieldsspiro-lactone 58, which upon acidic cleavage of the Boc group providesthe desired pyrrolidine 59.

Spiro-pyrrolidine 64 can be prepared according to the method outlined inScheme 16.

A series of aromatic piperazine intermediates 69 can be preparedaccording to Scheme 17 (X is e.g., Cl, Br, I, OTf, etc.; R′ is, e.g., H,F, Cl, Me, CF₃, OCF₃, etc.; R″ is, e.g., CO₂R, CN, C(O)NR³R⁴, etc.; R ise.g., alkyl, cycloalkyl, etc.; and J is, e.g., CH or N) by reactingBoc-piperazine 65 with a variety of boronic acids 66 under the catalysisof copper (II) acetate (Combs, A. P.; Tadesse, S.; Rafalski, M.; Haque,T. S.; Lam, P. Y. S. J. Comb. Chem. 2002, 4, 179) or with a variety ofaryl or heteroaryl halides 67 using Buchwald/Hartwig conditions (Louie,J; Hartwig, J. F. Tetrahedron Lett. 1995, 36, 3609 & Bolm, C. et al. J.Org. Chem. 2005, 70, 2346.). Aromatic piperazine intermediates 69 canalso be prepared through classical ring closure of appropriatelysubstituted anilines and bis-(2-chloroethyl)amine hydrochloride in thepresence of base (E. Mishani, et. al. Tetrahedron Lett. 1996, 37, 319),or through direct nucleophilic aromatic substitution of the piperazine(S. M. Dankwardt, et al., Tetrahedron Lett. 1995, 36, 4923). Afterremoval of the Boc group with TFA, the secondary amine 69 can be coupledwith sulfonyl chlorides, acyl chlorides, carboxylic acids, alkylhalides, or undergo reductive amination by using procedures known tothose skilled in the art.

Amines can be coupled to the pyridyl halide 67 in the absence of apalladium catalyst by heating the two reagents in DMSO as outlined inScheme 18 (X is, e.g., Cl, Br, etc.; R′ is, e.g., H, F, Cl, Me, CF₃,OCF₃, etc.; R″ is, e.g., CO₂R, CN, C(O)NR³R⁴, etc.; R is, e.g., alkyl,cycloalkyl, etc.; R* and R** are independently, e.g., H, alkyl,cycloalkyl, etc.; von Geldern, Thomas W. et al. Biorg. & Med. Chem.Lett. 2005, 15, 195).

A series of aryl tetrahydropyridines 73 can be prepared by firstconverting the tert-butoxycarbonyl-piperid-4-one 71 to the correspondingenol triflate 74 using LDA and N-phenyltrifluoromethanesulfonamideaccording to Scheme 19 (M is Li, Na, MgBr; X is, e.g., Cl, Br, I, OTf,etc.; R′ is, e.g., H, F, Cl, Me, CF₃, OCF₃, etc.; R″ is, e.g., CO₃R, CN,C(O)NR³R⁴, etc.; R is, e.g., alkyl, cycloalkyl, etc.; J is CH or N). Theenol triflate can then be used directly in a Suzuki-type couplingreaction with a variety of aromatic boronic acids 66 to produce thearyl- or heteroaryl-tetrahydropyridines 76 (M. G. Bursavich, D. H. Rich,Org. Lett. 2001, 3, 2625). Alternatively, the enol triflate can beconverted to the corresponding enol boronic ester 75 or acid viapalladium mediated coupling and then subsequently coupled with an arylhalide through a Suzuki-type reaction.

After removal of the Boc group of compound 76 with TFA, the secondaryamine 73 can be coupled with sulfonyl chlorides, acyl chlorides,carboxylic acids, alkyl halides, or undergo reductive amination by usingprocedures known to those skilled in the art.

Aromatic tetrahydropyridines 73 can also be prepared through alternativemethods known by those skilled in the art of organic synthesis, such asdirect nucleophilic addition of an aryl or heteroaryl anion 72 to apiperidone 71 followed by dehydration and deprotection of the resultantalcohol compound.

A series of aromatic piperidine derivatives 78 can be prepared accordingto Scheme 20 (X is, e.g., Cl, Br, I, OTf, etc.; R′ is, e.g., H, F, Cl,Me, CF₃, OCF₃, etc.; R″ is, e.g., CO₂R, CN, C(O)NR³R⁴, etc.; R is, e.g.,alkyl, cycloalkyl, etc.; J is CH or N) by catalytic hydrogenation of theabove formed aryl- or heteroaryl-tetrahydropyridines 73 or by coupling4-bromopyridine with an aromatic boronic acid 66 in the presence of apalladium catalyst followed by hydrogenation. The resulting secondaryamine 78 can then be coupled with sulfonyl chlorides, acyl chlorides,carboxylic acids, alkyl halides, or undergo reductive amination by usingprocedures known to those skilled in the art.

In addition to using the Buckwald/Hartwig conditions described above toform the C—N bond, copper (1) mediated coupling reactions can be usedwhen the amine is α to an sp² carbon such as in the case of a pyrrazole,oxazolidin-2-one, 2-oxo-pyrrolidine, imidazole, indazole,1H-benzimidazole, pyrid-2-one, t-butyl carbamate, etc. according toScheme 21 (X is, e.g., Cl, Br, I, OTf, etc.; Q is O, S or CH₂; R′ is,e.g., H, F, Cl, Me, CF₃, OCF₃, etc.; R″ is, e.g., CO₂R, CN, C(O)NR³R⁴,etc.; R is, e.g., alkyl, cycloalkyl, etc.; J is CH or N; R* and R** areindependently H, alkyl, cycloalkyl, etc.); Woolven, James M. et al. J.Med. Chem. 2003, 46, 4428).

A series of piperidinyl, 1,2,3,6-tetrahydropyridinyl, and piperazinylderivatives 82-85 can be prepared by sulfonylation 82, acylation 83,alkylation 84 or reductive amination 85 of the secondary amine 81 asoutlined below in Scheme 22 (R″ is, e.g., CO₂R, CN, C(O)NR³R⁴, etc.; Ris, e.g., alkyl, cycloalkyl, etc.; Q is N or CH; R^(aa), R^(bb), ROC,R^(dd) are, for example, alkyl, cycloalkyl, aryl, heterocycloalkyl,heteroaryl, heterocycloalkyl and derivatives thereof).

Methods

Compounds of the invention can modulate activity of 11βHSD1 and/or MR.The term “modulate” is meant to refer to an ability to increase ordecrease activity of an enzyme or receptor. Accordingly, compounds ofthe invention can be used in methods of modulating 11βHSD1 and/or MR bycontacting the enzyme or receptor with any one or more of the compoundsor compositions described herein. In some embodiments, compounds of thepresent invention can act as inhibitors of 11βHSD1 and/or MR. In furtherembodiments, the compounds of the invention can be used to modulateactivity of 11βHSD1 and/or MR in an individual in need of modulation ofthe enzyme or receptor by administering a modulating amount of acompound of the invention.

The present invention further provides methods of inhibiting theconversion of cortisone to cortisol in a cell, or inhibiting theproduction of cortisol in a cell, where conversion to or production ofcortisol is mediated, at least in part, by 11βHSD1 activity. Methods ofmeasuring conversion rates of cortisone to cortisol and vice versa, aswell as methods for measuring levels of cortisone and cortisol in cells,are routine in the art.

The present invention further provides methods of increasing insulinsensitivity of a cell by contacting the cell with a compound of theinvention. Methods of measuring insulin sensitivity are routine in theart.

The present invention further provides methods of treating diseaseassociated with activity or expression, including abnormal activity andoverexpression, of 11βHSD1 and/or MR in an individual (e.g., patient) byadministering to the individual in need of such treatment atherapeutically effective amount or dose of a compound of the presentinvention or a pharmaceutical composition thereof. Example diseases caninclude any disease, disorder or condition that is directly orindirectly linked to expression or activity of the enzyme or receptor.An 11βHSD1-associated disease can also include any disease, disorder orcondition that can be prevented, ameliorated, or cured by modulatingenzyme activity.

Examples of 11βHSD1-associated diseases include obesity, diabetes,glucose intolerance, insulin resistance, hyperglycemia, hypertension,hyperlipidemia, cognitive impairment, dementia, glaucoma, cardiovasculardisorders, osteoporosis, and inflammation. Further examples of11βHSD1-associated diseases include metabolic syndrome, type 2 diabetes,androgen excess (hirsutism, menstrual irregularity, hyperandrogenism)and polycystic ovary syndrome (PCOS).

The present invention further provides methods of modulating MR activityby contacting the MR with a compound of the invention, pharmaceuticallyacceptable salt, prodrug, or composition thereof. In some embodiments,the modulation can be inhibition. In further embodiments, methods ofinhibiting aldosterone binding to the MR (optionally in a cell) areprovided. Methods of measuring MR activity and inhibition of aldosteronebinding are routine in the art.

The present invention further provides methods of treating a diseaseassociated with activity or expression of the MR. Examples of diseasesassociated with activity or expression of the MR include, but are notlimited to hypertension, as well as cardiovascular, renal, andinflammatory pathologies such as heart failure, atherosclerosis,arteriosclerosis, coronary artery disease, thrombosis, angina,peripheral vascular disease, vascular wall damage, stroke, dyslipidemia,hyperlipoproteinaemia, diabetic dyslipidemia, mixed dyslipidemia,hypercholesterolemia, hypertriglyceridemia, and those associated withtype 1 diabetes, type 2 diabetes, obesity metabolic syndrome, insulinresistance and general aldosterone-related target organ damage.

As used herein, the term “cell” is meant to refer to a cell that is invitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can bepart of a tissue sample excised from an organism such as a mammal. Insome embodiments, an in vitro cell can be a cell in a cell culture. Insome embodiments, an in vivo cell is a cell living in an organism suchas a mammal. In some embodiments, the cell is an adipocyte, a pancreaticcell, a hepatocyte, neuron, or cell comprising the eye.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” the 11βHSD1 enzyme with a compound of theinvention includes the administration of a compound of the presentinvention to an individual or patient, such as a human, having 11βHSD1,as well as, for example, introducing a compound of the invention into asample containing a cellular or purified preparation containing the11βHSD1 enzyme.

As used herein, the term “individual” or “patient,” usedinterchangeably, refers to any animal, including mammals, preferablymice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, or primates, and most preferably humans.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response that is being sought in a tissue,system, animal, individual or human by a researcher, veterinarian,medical doctor or other clinician, which includes one or more of thefollowing:

(1) preventing the disease; for example, preventing a disease, conditionor disorder in an individual who may be predisposed to the disease,condition or disorder but does not yet experience or display thepathology or symptomotology of the disease (non-limiting examples arepreventing metabolic syndrome, hypertension, obesity, insulinresistance, hyperglycemia, hyperlipidemia, type 2 diabetes, androgenexcess (hirsutism, menstrual irregularity, hyperandrogenism) andpolycystic ovary syndrome (PCOS);

(2) inhibiting the disease; for example, inhibiting a disease, conditionor disorder in an individual who is experiencing or displaying thepathology or symptomotology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomotology)such as inhibiting the development of metabolic syndrome, hypertension,obesity, insulin resistance, hyperglycemia, hyperlipidemia, type 2diabetes, androgen excess (hirsutism, menstrual irregularity,hyperandrogenism) or polycystic ovary syndrome (PCOS), stabilizing viralload in the case of a viral infection; and

(3) ameliorating the disease; for example, ameliorating a disease,condition or disorder in an individual who is experiencing or displayingthe pathology or symptomotology of the disease, condition or disorder(i.e., reversing the pathology and/or symptomotology) such as decreasingthe severity of metabolic syndrome, hypertension, obesity, insulinresistance, hyperglycemia, hyperlipidemia, type 2 diabetes, androgenexcess (hirsutism, menstrual irregularity, hyperandrogenism) andpolycystic ovary syndrome (PCOS), or lowering viral load in the case ofa viral infection.

Pharmaceutical Formulations and Dosage Forms

When employed as pharmaceuticals, the compounds of Formula I can beadministered in the form of pharmaceutical compositions. Thesecompositions can be prepared in a manner well known in thepharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is desired and uponthe area to be treated. Administration may be topical (includingophthalmic and to mucous membranes including intranasal, vaginal andrectal delivery), pulmonary (e.g., by inhalation or insufflation ofpowders or aerosols, including by nebulizer; intratracheal, intranasal,epidermal and transdermal), ocular, oral or parenteral. Methods forocular delivery can include topical administration (eye drops),subconjunctival, periocular or intravitreal injection or introduction byballoon catheter or ophthalmic inserts surgically placed in theconjunctival sac. Parenteral administration includes intravenous,intraarterial, subcutaneous, intraperitoneal or intramuscular injectionor infusion; or intracranial, e.g., intrathecal or intraventricular,administration. Parenteral administration can be in the form of a singlebolus dose, or may be, for example, by a continuous perfusion pump.Pharmaceutical compositions and formulations for topical administrationmay include transdermal patches, ointments, lotions, creams, gels,drops, suppositories, sprays, liquids and powders. Conventionalpharmaceutical carriers, aqueous, powder or oily bases, thickeners andthe like may be necessary or desirable.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, one or more of the compounds of the inventionabove in combination with one or more pharmaceutically acceptablecarriers. In making the compositions of the invention, the activeingredient is typically mixed with an excipient, diluted by an excipientor enclosed within such a carrier in the form of, for example, acapsule, sachet, paper, or other container. When the excipient serves asa diluent, it can be a solid, semi-solid, or liquid material, which actsas a vehicle, carrier or medium for the active ingredient. Thus, thecompositions can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,aerosols (as a solid or in a liquid medium), ointments containing, forexample, up to 10% by weight of the active compound, soft and hardgelatin capsules, suppositories, sterile injectable solutions, andsterile packaged powders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g. about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 100 mg, more usually about 10 to about30 mg, of the active ingredient. The term “unit dosage forms” refers tophysically discrete units suitable as unitary dosages for human subjectsand other mammals, each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient.

The active compound can be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, 0.1 to about 500 mg of the activeingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions in can be nebulized by use of inert gases. Nebulizedsolutions may be breathed directly from the nebulizing device or thenebulizing device can be attached to a face masks tent, or intermittentpositive pressure breathing machine. Solution, suspension, or powdercompositions can be administered orally or nasally from devices whichdeliver the formulation in an appropriate manner.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of the compounds of the present invention canvary according to, for example, the particular use for which thetreatment is made, the manner of administration of the compound, thehealth and condition of the patient, and the judgment of the prescribingphysician. The proportion or concentration of a compound of theinvention in a pharmaceutical composition can vary depending upon anumber of factors including dosage, chemical characteristics (e.g.,hydrophobicity), and the route of administration. For example, thecompounds of the invention can be provided in an aqueous physiologicalbuffer solution containing about 0.1 to about 10% w/v of the compoundfor parenteral administration. Some typical dose ranges are from about 1μg/kg to about 1 g/kg of body weight per day. In some embodiments, thedose range is from about 0.01 mg/kg to about 100 mg/kg of body weightper day. The dosage is likely to depend on such variables as the typeand extent of progression of the disease or disorder, the overall healthstatus of the particular patient, the relative biological efficacy ofthe compound selected, formulation of the excipient, and its route ofadministration. Effective doses can be extrapolated from dose-responsecurves derived from in vitro or animal model test systems.

The compounds of the invention can also be formulated in combinationwith one or more additional active ingredients which can include anypharmaceutical agent such as anti-viral agents, antibodies, immunesuppressants, anti-inflammatory agents and the like.

Labeled Compounds and Assay Methods

Another aspect of the present invention relates to radio-labeledcompounds of the invention that would be useful not only inradio-imaging but also in assays, both in vitro and in vivo, forlocalizing and quantitating the enzyme in tissue samples, includinghuman, and for identifying ligands by inhibition binding of aradio-labeled compound. Accordingly, the present invention includesenzyme assays that contain such radio-labeled compounds.

The present invention further includes isotopically-labeled compounds ofthe invention. An “isotopically” or “radio-labeled” compound is acompound of the invention where one or more atoms are replaced orsubstituted by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). Suitable radionuclides that may be incorporated incompounds of the present invention include but are not limited to ²H(also written as D for deuterium), ³H (also written as T for tritium),¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br,⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. The radionuclide that isincorporated in the instant radio-labeled compounds will depend on thespecific application of that radio-labeled compound. For example, for invitro receptor labeling and competition assays, compounds thatincorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I, ¹³¹I, ³⁵S or will generally be mostuseful. For radio-imaging applications ¹¹C, ¹⁸F, ¹²⁵I, ¹²³I, ¹²⁴I, ¹³¹I,⁷⁵Br, ⁷⁶Br or ⁷⁷Br will generally be most useful.

It is understood that a “radio-labeled” or “labeled compound” is acompound that has incorporated at least one radionuclide. In someembodiments the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br.

Synthetic methods for incorporating radio-isotopes into organiccompounds are applicable to compounds of the invention and are wellknown in the art.

A radio-labeled compound of the invention can be used in a screeningassay to identify/evaluate compounds. In general terms, a newlysynthesized or identified compound (i.e., test compound) can beevaluated for its ability to reduce binding of the radio-labeledcompound of the invention to the enzyme. Accordingly, the ability of atest compound to compete with the radio-labeled compound for binding tothe enzyme directly correlates to its binding affinity.

Kits

The present invention also includes pharmaceutical kits useful, forexample, in the treatment or prevention of 11βHSD1-associated diseasesor disorders, obesity, diabetes and other diseases referred to hereinwhich include one or more containers containing a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof the invention. Such kits can further include, if desired, one or moreof various conventional pharmaceutical kit components, such as, forexample, containers with one or more pharmaceutically acceptablecarriers, additional containers, etc., as will be readily apparent tothose skilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, canalso be included in the kit.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of noncriticalparameters which can be changed or modified to yield essentially thesame results.

EXAMPLES Example 1(3S)-1-((1-(4-Chlorophenyl)cyclopropyl)carbonyl)pyrrolidin-3-ol

To a solution of 1-(4-chlorophenyl)cyclopropanecarboxylic acid (50 mg,0.25 mmol), (3S)-pyrrolidin-3-ol (24.4 mg, 0.28 mmol) and BOP (116.0 mg,0.26 mmol) in 0.4 mL DMF was added hunig base (0.066 ml, 0.38 mmol). Themixture was stirred at room temperature overnight and directly purifiedby prep. HPLC to provide(3S)-1-((1-(4-chlorophenyl)cyclopropyl)carbonyl)pyrrolidin-3-ol (20 mg).LCMS: m/z 266.0 (M+H)*; 553.1 (2M+Na)⁺.

Example 2 (3S)-1-[(1-Phenylcyclopropyl)carbonyl]pyrrolidin-3-ol

This compound was prepared using procedures analogous to those describedfor Example 1. LCMS: m/z 232.1 (M+H)⁺.

Example 3 (3R)-1-[(1-Phenylcyclopropyl)carbonyl]pyrrolidin-3-ol

This compound was prepared using procedures analogous to those describedfor Example 1. LCMS: m/z 232.1 (M+H)⁺.

Example 41-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-2-phenylpyrrolidine

To a solution of 30 mg of 1-(4-chlorophenyl)cyclopropanecarboxylic acidand 81 mg BOP reagent in 0.5 mL methylene chloride wad added 27 mg of2-phenylpyrrolidine, followed by the addition of 53 ul of Hunig base.The reaction mixture was stirred at r.t. for 2 hours and directlypurified by flash column using ethyl/hexane as the eluting solvent toprovide the desired1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}-2-phenylpyrrolidine. LCMS(ESI): 326.1 (M+H⁺).

Example 51′-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-2,3-dihydrospiro[indene-1,4′-piperidine]

This compound was prepared using procedures analogous to those describedfor Example 4.

Example 6 1-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-3-phenylpiperidine

This compound was prepared using procedures analogous to those describedfor Example 4. (ESI): 340.1 (M+H⁺). Cal. MS: 339.1 Ms(ESI):(M+H)⁺=340.1.

Example 71-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-4-phenylpiperidine-4-carbonitrile

This compound was prepared using procedures analogous to those describedfor Example 4. (ESI): 365.0 (M+H⁺).

Example 81-{[(1-(4-Chlorophenyl)cyclopropyl]carbonyl}-4-phenoxypiperidine

This compound was prepared using procedures analogous to those describedfor Example 4. (ESI): 356.0 (M+H⁺).

Example 91′-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}-1-methylspiro[indole-3,4′-piperidin]-2(1H)-one

This compound was prepared using procedures analogous to those describedfor Example 4. (ESI): 395.1 (M+H⁺).

Example 101-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-4-phenylpiperidin-4-ol

This compound was prepared using procedures analogous to those describedfor Example 4. (ESI): 356.1 (M+H⁺).

Example 11 Methyl3-(1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}piperidin-4-yl)benzoate

This compound was prepared using procedures analogous to those describedfor Example 4. (ESI): 398.1 (M+H⁺).

Example 124-Benzyl-1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}piperidin-4-ol

This compound was prepared using procedures analogous to those describedfor Example 4. (ESI): 370.1 (M+H⁺).

Example 134-(4-tert-Butyl-1,3-thiazol-2-yl)-1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}piperidine

This compound was prepared using procedures analogous to those describedfor Example 4. (ESI): 403.1 (M+H⁺).

Example 14 Methyl4-(1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}piperidin-4-yl)benzoate

This compound was prepared using procedures analogous to those describedfor Example 4. (ESI): 398.1 (M+H⁺).

Example 15 tert-Butyl1′-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}spiro[indole-3,4′-piperidine]-1(2H)-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 4. (ESI): 467.1 (M+H⁺).

Example 161′-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]

This compound was prepared using procedures analogous to those describedfor Example 1. (ESI): 381.1 (M+H⁺).

Example 178-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-3-phenyl-1-oxa-2,8-diazaspiro[4.5]dec-2-ene

This compound was prepared using procedures analogous to those describedfor Example 1. (ESI): 395.1 (M+H⁺).

Example 181-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-4-[3-(trifluoromethyl)phenyl]piperidine

This compound was prepared using procedures analogous to those describedfor Example 4. (ESI): 408.1 (M+H⁺).

Example 191-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-4-(4-phenyl-1,3-thiazol-2-yl)piperidine

This compound was prepared using procedures analogous to those describedfor Example 1. (ESI): 423.1 (M+H⁺).

Example 20 tert-Butyl7-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}-2,7-diazaspiro[4.5]decane-2-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 1. Ms(ESI): (M+Na)+=441.2, 363.0 (M−^(t)Bu).

Example 21 tert-Butyl1′-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}-1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 1. (ESI): 481.2 (M+H⁺).

Example 22 tert-Butyl7-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}-2,7-diazaspiro[3.5]nonane-2-carboxylate

This compound was prepared using procedures analogous to those describedfor Example 1. (ESI): 405.1 (M+H⁺), 349.1 (M−^(τ)Bu).

Example 234-(1-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}pyrrolidin-3-yl)pyridine

This compound was prepared using procedures analogous to those describedfor example 1. LCMS (ESI): 327.1 (M+H⁺).

Example 244-((3S)-1-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}pyrrolidin-3-yl)pyridine

This compound was obtained by chiral HPLC purification of4-(1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}pyrrolidin-3-yl)pyridineof Example 23. LCMS (ESI): 327.0 (M+H⁺).

Example 254-((3R)-1-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}pyrrolidin-3-yl)pyridine

This compound was obtained by chiral HPLC purification of4-(1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}pyrrolidin-3-yl)pyridine.LCMS (ESI): 327.0 (M+H⁺).

Example 261-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-3-phenylpyrrolidine

This compound was prepared using procedures analogous to those describedfor Example 4. LCMS (ESI): 326.1 (M+H⁺).

Example 272-(1-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}pyrrolidin-3-yl)pyrazine

This compound was prepared using procedures analogous to those describedfor Example 4. LCMS (ESI): 328.0 (M+H⁺).

Example 283-(1-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}pyrrolidin-3-yl)pyridine

This compound was prepared using procedures analogous to those describedfor Example 4. LCMS (ESI): 327.0 (M+H⁺).

Example 29(3R)-1-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-3-phenylpyrrolidine

This compound was prepared using procedures analogous to those describedfor example 4. LCMS (ESI): 326.0 (M+H⁺).

Example 303-(3-Chlorophenyl)-1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}pyrrolidine

This compound was prepared using procedures analogous to those describedfor example 4. LCMS (ESI): 360.0 (M+H⁺).

Example 311-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}-3-[3-(trifluoromethyl)phenyl]pyrrolidine

This compound was prepared using procedures analogous to those describedfor example 4. LCMS (ESI): 394.0 (M+H⁺).

Example 322-(1-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}pyrrolidin-3-yl)pyridine

This compound was prepared using procedures analogous to those describedfor example 4. LCMS (ESI): 327.1 (M+H⁺).

Example 331-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-3-phenylpyrrolidin-3-ol

This compound was prepared using procedures analogous to those describedfor example 1. LCMS (ESI): 342.1 (M+H⁺).

Example 341-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-3-(2-naphthyl)pyrrolidine

This compound was prepared using procedures analogous to those describedfor example 4. LCMS (ESI): 376.1 (M+H⁺).

Example 353-Benzyl-1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}pyrrolidine

This compound was prepared using procedures analogous to those describedfor example 4. LCMS (ESI): 340.1 (M+H⁺).

Example 361-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-3-(phenylsulfonyl)pyrrolidine

This compound was prepared using procedures analogous to those describedfor example 4. LCMS (ESI): 390.1 (M+H⁺).

Example 372-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-5-(4-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptane

This compound was prepared using procedures analogous to those describedfor example 1. LCMS (ESI): 371.1 (M+H⁺).

Example 381-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-3-(4-phenoxyphenyl)pyrrolidine

This compound was prepared using procedures analogous to those describedfor example 4. LCMS (ESI): 418.0 (M+H⁺).

Example 39 Methyl(3S,4R)-1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}-4-phenylpyrrolidine-3-carboxylate

This compound was prepared using procedures analogous to those describedfor example 4. LCMS (ESI): 384.1 (M+H⁺).

Example 401-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-3-(4-methoxyphenyl)pyrrolidine

This compound was prepared using procedures analogous to those describedfor example 4. LCMS: m/z 356.1 (M+H)⁺.

Example 411-((1-(4-chlorophenyl)cyclopropyl)carbonyl)-3-(4-trifluorophenyl)pyrrolidine

This compound was prepared using procedures analogous to those describedfor example 4. LCMS: m/z 394.0 (M+H)⁺.

Example 423-(4-chlorophenyl)-1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}pyrrolidine

This compound was prepared using procedures analogous to those describedfor example 4. LCMS: m/z 360.0 (M+H)⁺; 382.0 (M+Na)⁺.

Example 434-(1-{[1-(2,4-dichlorophenyl)cyclopropyl]carbonyl}pyrrolidin-3-yl)pyridine

This compound was prepared using procedures analogous to those describedfor example 4. LCMS: m/z 361.0 (M+); 384.0 (M+Na)⁺.

Example 444-(1-{[1-(4-methoxyphenyl)cyclopropyl]carbonyl}pyrrolidin-3-yl)pyridine

This compound was prepared using procedures analogous to those describedfor example 4. LCMS: m/z 323.1 (M+H)⁺; 345.0 (M+Na)⁺.

Example 454-(1-{[1-(4-Methylphenyl)cyclopropyl]carbonyl}pyrrolidin-3-yl)pyridine

This compound was prepared using procedures analogous to those describedfor example 4. LCMS: m/z 307.1 (M+H)⁺; 329.1 (M+Na)⁺.

Example 461-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-4-phenylpiperidine

This compound was prepared using procedures analogous to those describedfor example 4. LCMS: m/z 340.1 (M+H)⁺; 362.1 (M+Na)⁺; 701.2 (2M+Na)⁺.

Example 473-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]isoquinoline

This compound was prepared using procedures analogous to those describedfor example 4. LCMS: (M+H)⁺=366.0/368.1.

Example 482-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole

This compound was prepared using procedures analogous to those describedfor example 4. LCMS: (M+H)⁺=352.1/354.0.

Example 492-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

This compound was prepared using procedures analogous to those describedfor example 4. LCMS: (M+H)*=338.0/340.0.

Example 501′-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-1,3-dihydrospiro[indene-2,4′-piperidine]

This compound was prepared using procedures analogous to those describedfor example 4. LCMS: (M+H)⁺=366.1/368.1.

Example 523-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoline

This compound was prepared using procedures analogous to those describedfor example 4. LCMS: (M+H)⁺=367.1/369.1.

Example 532-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole

This compound was prepared using procedures analogous to those describedfor example 4, LCMS: (M+H)⁺=353.1/355.1

Example 541′-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}spiro[chromene-2,4′-piperidine]

This compound was prepared using procedures analogous to those describedfor example 4, LCMS: (M+H)⁺=380.1/382.1.

Example 551′-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,4′-piperidine]

This compound was prepared using procedures analogous to those describedfor example 4, LCMS: (M+H)⁺=368.1/369.2.

Example 561′-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}spiro[indole-3,4′-piperidin]-2(1H)-one

This compound was prepared using procedures analogous to those describedfor example 4, LCMS: (M+H)⁺=381.0/383.0.

Example 578-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-2,8-diazaspiro[4.5]decan-3-one

This compound was prepared using procedures analogous to those describedfor example 4, LCMS: (M+H)⁺=333.0/335.1.

Example 582-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-1,2,3,4-tetrahydroisoquinoline

This compound was prepared using procedures analogous to those describedfor example 4.

Example 596-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-4,5,6,7-tetrahydrothieno[2,3-c]pyridine

This compound was prepared using procedures analogous to those describedfor example 4, LCMS: (M+H)⁺=318.0/320.0.

Example 60 1-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}indoline

This compound was prepared using procedures analogous to those describedfor example 4, LCMS: (M+H)⁺=298.0/300.0.

Example 61 2-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}isoindoline

This compound was prepared using procedures analogous to those describedfor example 4, LCMS: (M+H)⁺=298.0/300.0.

Example 628-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one

This compound was prepared using procedures analogous to those describedfor example 4, LCMS: (M+H)⁺=410.1/412.1.

Example 634-Benzylidene-1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}piperidine

This compound was prepared using procedures analogous to those describedfor example 4, LCMS: (M+H)⁺=352.1/354.1.

Example 641′-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-1,4′-bipiperidine

This compound was prepared using procedures analogous to those describedfor example 4, LCMS: (M+H)⁺=347.2/349.2.

Example 654-(1-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}piperidin-4-yl)pyridine

This compound was prepared using procedures analogous to those describedfor example 4, LCMS: (M+H)⁺=341.1/343.1.

Example 661-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-3-(4-fluorophenyl)pyrrolidine

This compound was prepared using procedures analogous to those describedfor example 4, LCMS: (M+H)⁺=344.1/346.1.

Example 671-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-3-(3-fluorophenyl)pyrrolidine

This compound was prepared using procedures analogous to those describedfor example 4, LCMS: (M+H)⁺=344.1/346.1.

Example 68N-(1-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}piperidin-4-yl)-N-phenylpropanamide

This compound was prepared using procedures analogous to those describedfor example 4, LCMS: (M+H)⁺=411.2/413.2.

Example 692-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}octahydropyrrolo[1,2-a]pyrazine

This compound was prepared using procedures analogous to those describedfor example 4, LCMS: (M+H)⁺=305.2/307.1.

Example 704-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}piperazine-1-carbaldehyde

This compound was prepared using procedures analogous to those describedfor example 4, LCMS: (M+H)⁺=293.1/295.1.

Example 714-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-2-methyl-1-phenylpiperazine

This compound was prepared using procedures analogous to those describedfor example 4, LCMS: (M+H)⁺=355.2/357.2.

Example 721-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-4-(pyridin-4-ylmethyl)piperazine

This compound was prepared using procedures analogous to those describedfor example 4, LCMS: (M+H)⁺=356.1/358.1.

Example 731-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-4-(2-thienylsulfonyl)piperazine

This compound was prepared using procedures analogous to those describedfor example 4, LCMS: (M+H)⁺=411.0/412.9.

Example 742-(1-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}piperidin-2-yl)ethanol

This compound was prepared using procedures analogous to those describedfor example 4, LCMS: (M+H)⁺=308.1/310.0.

Example 752-(1-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}piperidin-4-yl)ethanol

This compound was prepared using procedures analogous to those describedfor example 4, LCMS: (M+H)⁺=308.1/310.0.

Example 761-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-4-(4-fluorophenyl)piperidine

This compound was prepared using procedures analogous to those describedfor example 4, LCMS: (M+H)⁺=358.1/360.1.

Example 774-(4-Chlorophenyl)-1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}-1,2,3,6-tetrahydropyridine

This compound was prepared using procedures analogous to those describedfor example 4, LCMS: (M+H)⁺=372.1/374.1.

Example 78(1-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}piperidin-2-yl)methanol

This compound was prepared using procedures analogous to those describedfor example 4, LCMS: (M+H)⁺=294.1/296.1.

Example 792-(1-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}pyrrolidin-2-yl)ethanol

This compound was prepared using procedures analogous to those describedfor example 4, LCMS: (M+H)⁺=294.1/296.1.

Example 80((2S)-1-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}pyrrolidin-2-yl)methanol

This compound was prepared using procedures analogous to those describedfor example 4, LCMS: (M+H)⁺=280.1/282.1.

Example 81((2R)-1-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}pyrrolidin-2-yl)methanol

This compound was prepared using procedures analogous to those describedfor example 4, LCMS: (M+H)⁺=280.0/282.0.

Example 821′-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}spiro[1,2-benzisothiazole-3,3′-pyrrolidine]1,1-dioxideStep 1: Synthesis of N-(tert-butyl)benzenesulfonamide

To a solution of benzenesulfonyl chloride (722 μL, 0.00566 mol),potassium carbonate (0.939 g, 0.00679 mol) in acetonitrile (15 mL, 0.29mol) was added tert-butylamine (0.652 mL, 0.00623 mol). The resultingmixture was stirred at r.t. for 30 minutes, followed by filtration andconcentration. The resulting residue was diluted with ethyl acetate, andthe resulting solution was washed with water then with brine, then driedwith MgSO₄ followed by concentration. The crude material was purified byflash chromatography on silica gel with 40% AcOEt in hexanes to give thedesired compound (1.21 g, 85% yield). MS (ESI): 236.0 (M+Na⁺).

Step 2: Synthesis of2-(1-benzyl-3-hydroxypyrrolidin-3-yl)-N-(tert-butyl)benzenesulfonamide

To a solution of N-(tert-butyl)benzenesulfonamide (536 mg, 0.00251 mol)in ether (10 mL, 0.1 mol) was added 1.7 M of tert-butyllithium inpentane (4.4 mL) under nitrogen at −78° C. The mixture was stirred at−78 Celsius for 15 min, then at 0 Celsius for 1 hour, and then cooleddown to −78 Celsius again. A solution of 1-benzylpyrrolidin-3-one (400.0mg, 0.002283 mol) in ether (3 mL) was added to the above solution. Thereaction solution was stirred at ±78 Celsius for 2 hours, then quenchedwith saturated NH₄Cl aqueous solution, and then extracted with EtOAc.The organic phase was washed with brine, then dried over MgSO₄. Theresidue was purified by flash chromatography on silica gel column with30% AcOEt in hexanes to give the desired compound (350 mg, 39% yield).MS (ESI): 389.1 (M+

Step 3: Synthesis of1′-benzylspiro[1,2-benzisothiazole-3,3′-pyrrolidine]1,1-dioxide

To a solution of2-(1-benzyl-3-hydroxypyrrolidin-3-yl)-N-(tert-butyl)benzene sulfonamide(350 mg, 0.00090 mol) in acetonitrile (15 mL, 0.29 mol) were addedsodium iodide (418 mg, 0.00279 mol) and chlorotrimethylsilane (0.354 mL,0.00279 mol). The reaction mixture was refluxed under nitrogen for 1hour and then cooled down to room temperature, then quenched with 10%aqueous sodium thiosulfate solution (10 mL), and then extracted withEtOAc. The organic phase was washed with water then brine, and thendried over MgSO₄ followed by filtration. The filtrate was concentratedto give the desired compound (170 mg, 60% yield). MS (ESI): 315.0(M+H⁺).

Step 4: Synthesis ofspiro[1,2-benzisothiazole-3,3′-pyrrolidine]1,1-dioxide

To a solution ofr-benzylspiro[1,2-benzisothiazole-3,3′-pyrrolidine]1,1-dioxide (170 mg,0.00054 mol) in methanol were added Pd black (150 mg) and formic acid(0.2 mL, 0.005 mol). The resulting reaction mixture was refluxedovernight, then cooled to room temperature, and then filtered andconcentrated to give the desired compound (50 mg, 42% Yield). MS (ESI):225.1 (M+H⁺).

Step 5: Synthesis of1′-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}spiro[1,2-benzisothiazole-3,3′-pyrrolidine]1,1-dioxide

To a solution of 1-(4-chlorophenyl)cyclopropanecarboxylic acid (40.0 mg,0.000203 mol) in N,N-dimethylformamide (0.5 mL, 0.006 mol) at 0 Celsiuswere added spiro[1,2-benzisothiazole-3,3′-pyrrolidine]1,1-dioxide (45.6mg, 0.000203 mol) and benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (99.0 mg, 0.000224 mol). The reaction mixture wasstirred for 3 minutes, then N,N-Diisopropylethylamine (88.6 μL, 0.000508mol) was added. The solution was then stirred at r.t. overnight. Thecrude material was purified by prep-HPLC to give the desired compound.MS (ESI): 404.0 (M+H⁺).

Example 831′-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-oneStep 1: Synthesis of tert-butyl3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidine]-1′-carboxylate

To a solution of methyl-2-iodobenzoate (0.952 mL, 0.00648 mol) intetrahydrofuran (10 mL, 0.1 mol) at −40 Celsius was added 1.0 M ofisopropylmagnesium bromide in tetrahydrofuran (7.6 mL), and the mixturewas stirred at −40 Celsius for 1 hour. A solution of tert-butyl3-oxopyrrolidine-1-carboxylate (1000 mg, 0.005 mol) in THF (2 mL) wasadded to the above mixture, the resulting mixture was then warmed up tor.t and continued to be stirred at r. t. for 2 hours. The reaction wasquenched with small amount of brine, then extracted with ethyl acetate,and then dried over MgSO₄ and concentrated. The residue was purified byflash chromatography on silica gel column with 40% AcOEt in hexanes togive the desired compound (0.9 g, 60% yield). MS (ESI): 312.0 (M+

Step 2: Synthesis of 3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-onehydrochloride

Tert-butyl3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidine]-1′-carboxylate (900mg, 0.003 mol) was added to 4 M of HCl in 1,4-dioxane (5 mL). Thereaction mixture was stirred at room temperature for 60 min and thenconcentrated to give desired product (660 mg, 95% Yield). MS (ESI):190.1 (M+H⁺).

Step 3: Synthesis of1′-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared using procedures analogous to those describedin example 82 (Step 5). MS (ESI): 368.1 (M+

Example 841′-({1-[4-(Pyridin-2-yloxy)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared using procedures analogous to those forExample 83. MS (ESI): 427.1 (M+H⁺) 449.1 (M+

Example 851′-{[1-(4-Chlorophenyl)cyclobutyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared using procedures analogous to those forExample 83. MS (ESI): 382.1 (M+H⁺)

Example 861′-{[1-(4-Methylphenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared using procedures analogous to those forExample 83. MS (ESI): 348.1 (M+H⁺).

Example 871′-{[1-(4-Methoxyphenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidine]-3-one

This compound was prepared using procedures analogous to those forExample 83. MS (ESI): 364.1 (M+

Example 881′-{[1-(2,4-Dichlorophenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared using procedures analogous to those forExample 83. MS (ESI): 402.0 (M+

Example 891′-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidine]Step 1: Synthesis of 1-benzyl-3-[2-(hydroxymethyl)phenyl]pyrrolidin-3-ol

To a solution of (2-iodophenyl)methanol (5.88 g, 0.0251 mol) intetrahydrofuran (40 mL, 0.5 mol) at −78 Celsius was added 1.600 M ofn-butyllithium in hexane (31.7 mL). The mixture was stirred at −4celsius for 1 hour, then cooled to −78 Celsius. A solution of1-benzylpyrrolidin-3-one (3.67 mL, 0.0228 mol) in THF (2 mL) was addedto the above mixture, and the resulting mixture was stirred at −78Celsius for 2 hours. The reaction was quenched with small amount ofbrine, then extracted with ethyl acetate. The organic phase was driedover MgSO₄ and concentrated. The residue was purified by flashchromatography on silica gel column with 70% AcOEt in hexanes to givethe desired compound (3.5 g, 54% yield). MS (ESI): 284.1 (M+H⁺).

Step 2: Synthesis of 1′-benzyl-3H-spiro[2-benzofuran-1,3′-pyrrolidine]

Diethyl azodicarboxylate (4.44 mL, 0.0282 mol) in 1 ml of THF was addedto a mixture of 1-benzyl-3-[2-(hydroxymethyl)phenyl]pyrrolidin-3-ol(3.50 g, 0.0124 mol) and triphenylphosphine (7.40 g, 0.0282 mol) intetrahydrofuran (50 mL, 0.6 mol) at room temperature. The mixture wasstirred at room temperature overnight. The reaction solution wasconcentrated and the residue was flash chromatographed on silica gelcolumn with 50% AcOEt in hexanes to give the desired compound (1.5 g,46% yield). MS (ESI): 266.1 (M+H⁺).

Step 3: Synthesis of 3H-spiro[2-benzofuran-1,3′-pyrrolidine]

To a solution of r-benzyl-3H-spiro[2-benzofuran-1,3′-pyrrolidine] (200mg, 0.0008 mol) in methanol (10 mL) was added Pd/C (150 mg), and thesuspension was hydrogenated under H₂ (50 psi) overnight. The mixture wasfiltered and then concentrated to give the desired compound (110 mg, 92%yield). MS (ESI): 176.1 (M+H⁺).

Step 4: Synthesis of1′-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidine]

This compound was prepared using procedures analogous to those describedin Example 82 (Step 5). MS (ESI): 354.1 (M+H⁺).

Example 901′-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-7H-spiro[furo[3,4-b]pyridine-5,3′-pyrrolidin]-7-oneStep 1: Synthesis of 7H-spiro[furo[3,4-b]pyridine-5,3′-pyrrolidin]-7-one

A solution of 2,2,6,6-tetramethyl-piperidine (0.820 mL, 0.00486 mol) intetrahydrofuran (5 mL, 0.06 mol) at −75 Celsius was added to 1.600 M ofn-butyllithium in hexane (4.05 mL). After the mixture was stirred for 15min, a solution of 2-pyridinecarboxylic acid (199 mg, 0.00162 mmol) wasadded. The resulting mixture was stirred at −75 Celsius for 10 minutes,then at −20 Celsius for 30 minutes. A solution of tert-butyl3-oxopyrrolidine-1-carboxylate (250 mg, 0.0013 mol) in THF (2 mL) wasthen added to the above mixture. The reaction mixture continued to bestirred at −20 Celsius for 20 minutes, then was warmed up to r.t. andthen stirred for additional 1 hour. The reaction mixture was quenchedwith water, then concentrated to remove THF, and then acidified to pH ˜1using 6M aqueous HCl solution, and then stirred at r.t. overnight. Theresulting mixture was extracted with methylene chloride. The aqueouslayer was concentrated and the residue was directly purified by flashchromatography on silica gel column with 10% methanol in methylenechloride to give the desired compound. MS (ESI): 190.9 (M+H⁺).

Step 2: Synthesis of1′-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}-7H-spiro[furo[3,4-b]pyridine-5,3′-pyrrolidin]-7-one

This compound was prepared using procedures analogous to those describedin Example 82 (Step 5). MS (ESI): 369.0 (M+H⁺).

Example 911′-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared using procedures analogous to Example 90. MS(ESI): 369.0 (M+H⁺).

Example 921′-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-1H-spiro[furo[3,4-c]pyridine-3,3′-pyrrolidin]-1-one

This compound was prepared using procedures analogous to example 90. MS(ESI): 369.0 (M+H⁺)

Example 931′-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}spiro[indole-3,3′-pyrrolidin]-2(1H)-oneStep 1: Synthesis of tert-butyl1,3,4,9-tetrahydro-2H-β-carboline-2-carboxylate

To a solution of 2,3,4,9-tetrahydro-1H-β-carboline (500 mg, 0.003 mol)in methylene chloride (10 mL, 0.2 mol) were addeddi-tert-butyldicarbonate (697 mg, 0.00319 mol) andN,N-diisopropylethylamine (0.607 mL, 0.00348 mol). The solution wasstirred at room temperature for 2 hours. The reaction solution wasdiluted with AcOEt, then washed with saturated aqueous NaHCO₃ solution,then dried with MgSO₄, and then concentrated to give desired compound(780 mg, 100% yield). MS (ESI): 273.0 (M+H⁺).

Step 2: Synthesis of tert-butyl2-methoxy-1′H-spiro[indole-3,3′-pyrrolidine]-1′-carboxylate

To a solution of tert-butyl1,3,4,9-tetrahydro-2H-β-carboline-2-carboxylate (780 mg, 0.0029 mol) inmethylene chloride (15 mL, 0.23 mol) was added triethylamine (0.439 mL,0.00315 mol). The solution was stirred at 5 Celsius under darkness andnitrogen. To the above solution with stirring, a solution of tert-butylhypochlorite (0.373 mL, 0.00329 mol) in CCl₄ (5 ml) was added dropwiseat 5 Celsius. The mixture was stirred at 5 Celsius until TLC showed thatstarting material was consumed.

The above mixture was then added to a solution of sodium hydroxide(1.146 g, 0.02864 mol) in methanol (50 mL, 1 mol) under reflux. Theresulting reaction mixture was under reflux overnight and thenconcentrated. The residue was diluted with AcOEt and water. The organicphase was washed with brine, then dried over MgSO₄ and concentrated. Theresidue was flash chromatographed on silica gel column with 50% AcOEt inhexanes to give the desired compound (660 mg, 76% yield). MS (ESI):303.0 (M+H⁺)

Step 3: Synthesis of spiro[indole-3,3′-pyrrolidin]-2(1H)-one

Tert-butyl 2-methoxy-1′H-spiro[indole-3,3′-pyrrolidine]-1′-carboxylate(660 mg, 0.0022 mol) was mixed with trifluoroacetic acid (1 mL) andwater (18 mL), and the mixture was stirred under reflux for 3 hours. Themixture was then cooled down to room temperature, then adjusted to basiccondition (pH ˜10) using ammonium hydroxide, and then extracted withCH₂Cl₃. The organic phase from the extraction was dried with MgSO₄, thenconcentrated to give the desired product (350 mg, 85% Yield). MS (ESI):189.0 (M+H⁺)

Step 4: Synthesis of1′-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}spiro[indole-3,3′-pyrrolidin]-2(1H)-one

This compound was prepared using procedures analogous to those describedin Example 82 (Step 5). MS (ESI): 367.0 (M+H⁺).

Example 94(1R)-1′-({1-[4-(1H-pyrazol-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-oneStep A: Butyl 1-[4-(1H-pyrazol-1-yl)phenyl]cyclopropanecarboxylate

A mixture of butyl 1-(4-bromophenyl)cyclopropanecarboxylate (297.2 mg,1.0 mmol), pyrrazole (102.1 mg, 1.5 mmol), copper iodide (9.6 mg, 0.050mmol), N,N′-Dimethyl-1,2-ethanediamine (11.0 μL, 0.103 mmol) andpotassium phosphate (430.0 mg, 2.026 mmol) in toluene (2.0 mL) wasdeaerated and charged with nitrogen. The resulting mixture was heated at100° C. overnight. Ethyl acetate (10 mL) was added to the mixture. Theresulting mixture was filtered through a pad of celite, and then washedwith ethyl acetate. The filtrate was concentrated and the residue waspurified by flash chromatography to give butyl1-[4-(1H-pyrazol-1-yl)phenyl]cyclopropanecarboxylate.

Step B: 1-[4-(1H-pyrazol-1-yl)phenyl]cyclopropanecarboxylic acid

Trifluoroacetic acid (1.0 mL) was added to butyl1-[4-(1H-pyrazol-1-yl)phenyl]cyclopropanecarboxylate (60 mg) inmethylene chloride (1.0 mL). The mixture was stirred at room temperatureovernight, and then concentrated to give a crude product which wasdirectly used in the reaction of next step without further purification.

Step C:(1R)-1′-({1-[4-(1H-pyrazol-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

4-Methylmorpholine (55 μL, 0.50 mmol) was added to a mixture of1-[4-(1H-pyrazol-1-yl)phenyl]cyclopropanecarboxylic acid (0.10 mmol),3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one dihydrochloride(0.026 g, 0.10 mmol), and BOP (0.057 g, 0.11 mmol) in DMF (1 mL). Themixture was stirred at room temperature for 2 hours, then adjusted to beacidic (pH=2.0) with TFA, and then diluted with DMF (0.8 mL). Theresulting solution was purified by a prep-LCMS followed by chiral HPLCto give(1R)-1′-({1-[4-(1H-pyrazol-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one(30%). MS (EST): (M+H)⁺=401.1

Example 95(1R)-1′-({1-[4-(Difluoromethoxy)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-oneStep A: 1-[4-(Difluoromethoxy)phenyl]cyclopropanecarboxylic acid

Sodium hydroxide [50% aqueous solution (3.20 g)], was added to a mixtureof [4-(difluoromethoxy)phenyl]acetonitrile (1.00 g, 5.4 mmol),benzyltriethylammonium chloride (0.10 g, 0.4 mmol) and1-bromo-2-chloro-ethane (1.58 g, 11.0 mmol) at 50° C. overnight.1,2-Ethanediol (10.00 mL) was then added to the mixture, and theresulting mixture was heated at 100° C. overnight. The mixture was thenpoured into ice-water (30 mL) and the resulting mixture was thenextracted with ethyl ether (2×10 mL). The aqueous phase was acidified(pH=2) with 1N aqueous HCl solution, and then was extracted with ethylacetate (4×15 mL). The combined organic phase was washed with brine (10mL), then dried over Na₂SO₄, then filtered, and then concentrated underreduced pressure. The residue was the desired product which was directlyused in the reaction of next step without furoom temperatureherpurification.

Step B:(1R)-1′-({1-[4-(difluoromethoxy)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

BOP (0.18 g, 0.42 mmol) was added to a mixture of1-[4-(difluoromethoxy)phenyl]cyclopropanecarboxylic acid (0.10 g, 0.46mmol) and 3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-onedihydrochloride (0.10 g, 0.38 mmol) in DMF (2.5 mL). After 5 min,4-methylmorpholine (0.2 mL, 2.0 mmol) was added to the mixture. Theresulting mixture was stirred at room temperature overnight, then wasadjusted to be acidic (pH=2.0) with TFA, and then was purified byprep-LCMS to give1′-({1-[4-(difluoromethoxy)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-oneTFA salt. The purified salt was neutralized by an addition of NaHCO₃aqueous solution (7.5%). The mixture was extracted with ethyl acetateand the organic phase was concentrated to give1′-({1-[4-(difluoromethoxy)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one.The desired stereo-isomer was isolated by chiral column to afford(1R)-1′-({1-[4-(difluoromethoxy)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one(49.5 mg, 31%).

Example 96(1R)-1′-{[1-(6-Phenylpyridin-3-yl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-oneStep 1. Benzyl 3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidine]-1′carboxylate

To a solution of methyl-2-iodobenzoate (8.8 mL, 0.060 mol) in THF (300mL) at −60° C. was slowly added a solution of isopropylmagnesium bromidein THF (1.0 M, 66.0 mL), and the mixture was stirred below −50° C. for 1h. A solution of benzyl-3-oxopyrrolidine-1-carboxylate (11.0 g, 0.05mol) in THF (20.0 mL) was added to the above mixture and the reactionmixture was stirred below −20° C. for 2 h. The reaction was quenched byan addition of saturated NH₄Cl aqueous solution, and the resultingmixture was extracted with ethyl acetate several times. The combinedextract was washed with water followed by brine, then dried and thenconcentrated. The product was purified by CombiFlash using Hexane/Ethylacetate.

Step 2. (1S)-(+)-10-Camphorsulfonicacid-3H-spiro-[2-benzofuran-1,3′-pyrrolidin]-3-one

Palladium on carbon (10%, 0.5 g) was added to a solution of benzyl3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidine]-1′ carboxylate (5.0 g,15.5 mmol) in methanol (100 mL) and the mixture was stirred underhydrogen balloon for 4 h (HPLC completion). The solvent of the mixturewas removed under vacuum. The residue was dissolved in acetonitrile (200mL), and (1S)-(+)-10-camphorsulfonic acid (3.6 g, 15.5 mmol) inacetonitrile (20 mL) was then slowly added at 50° C. The formed solidwas filtered and dried to give the desired product. LC-MS: 190.1 (M+H)⁺.

Step 3: Ethyl 1-(6-phenylpyridin-3-yl)cyclopropanecarboxylate

Sodium carbonate (42.4 mg, 0.400 mmol) in water (0.20 mL) was added to amixture of ethyl 1-(6-chloropyridin-3-yl)cyclopropanecarboxylate (45.1mg, 0.200 mmol), Phenylboronic acid (24.4 mg, 0.200 mmol) andtetrakis(triphenylphosphine)palladium(0) (7.15 mg) in toluene (200.0 μL)and ethanol (100.0 μL). The resulting mixture was irradiated bymicrowave at 120° C. for 15 minutes. Ethyl acetate (5 mL) was then addedto the mixture. The resulting mixture was washed with water followed bybrine. The organic layer was dried over Na₂SO₄, then filtered, and thenconcentrated under reduced pressure. The residue was purified by flashchromatography with ethyl acetate/hexane to give ethyl1-(6-phenylpyridin-3-yl)cyclopropanecarboxylate.

Step 4: 1-(6-Phenylpyridin-3-yl)cyclopropanecarboxylic acid

Lithium hydroxide, monohydrate (0.016 g, 0.37 mmol) was added to ethyl1-(6-phenylpyridin-3-yl)cyclopropanecarboxylate (50.0 mg, 0.19 mmol) inmethanol (1.5 mL) and water (0.5 mL). The mixture was stirred at roomtemperature for overnight, then was adjusted to be acidic (pH=5) with 1NHCl aqueous solution, and then was concentrated to give a crude productwhich was directly used in the reaction of the next step without furtherpurification.

Step 5:(1R)-1′-{[1-(6-Phenylpyridin-3-yl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

1-(6-Phenylpyridin-3-yl)cyclopropanecarboxylic acid was then coupledwith (1S)-(+)-10-camphorsulfonic acid salt of(1R)-3H-spiro-[2-benzofuran-1,3′-pyrrolidin]-3-one using proceduresanalogous to those of Example 83 to afford(1R)-1′-{[1-(6-Phenylpyridin-3-yl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one.MS (ESI): (M+H)⁺=411.1

Example 971′-{[1-(6-Phenylpyridin-3-yl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared using procedures analogous to those forexample 96. The yield: 40%. MS (ESI): (M+H)⁺=412.1

Example 98(1R)-1′-{[1-(4-Pyrrolidin-1-ylphenyl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-oneStep 1: tert-Butyl 1-(4-pyrrolidin-1-ylphenyl)cyclopropanecarboxylate

A mixture of tert-butyl 1-(4-bromophenyl)cyclopropanecarboxylate (297.1mg, 1.0 mmol), pyrrolidine (100.0 μL, 1.2 mmol), sodium tert-pentoxide(154.2 mg, 1.40 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (24.5 mg, 0.030 mmol) and1,1′-bis(diphenylphosphino)ferrocene (16.6 mg, 0.030 mmol) was deaeratedunder vacuum and then charged with nitrogen. To the mixture was addedtoluene (2.0 mL). The resulting mixture was heated at 100° C. forovernight. After cooling, the mixture was poured into ice-water and theresulting mixture was extracted with ethyl acetate (4×10 mL) Thecombined organic phase was washed with water and brine, then dried overNa₂SO₄, then filtered, and then concentrated under reduced pressure. Theresidue was purified by flash chromatography with ethyl acetate/hexaneto afford tert-butyl 1-(4-pyrrolidin-1-ylphenyl)cyclopropanecarboxylate.

Step 2:(1R)-1′-{[1-(4-pyrrolidin-1-ylphenyl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

The above material of tert-butyl1-(4-pyrrolidin-1-ylphenyl)cyclopropanecarboxylate was treated with TFAin methylene chloride to remove the tert-butyl group, the resulting acidwas then coupled with3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one dihydrochlorideusing procedures analogous to those for Example 94 to afford(1R)-1′-{[1-(4-pyrrolidin-1-ylphenyl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one.MS (ESI): (M+H)⁺=404.1

Example 99(1R)-1′-{[1-(4-Pyrrolidin-1-ylphenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared using procedures analogous to those forexample 96. The yield: 7%. MS (ESI): (M+H)⁺=403.1

Example 100(1R)-1′-{[1-(6-Pyrrolidin-1-ylpyridin-3-yl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-oneStep 1: Ethyl 1-(6-pyrrolidin-1-ylpyridin-3-yl)cyclopropanecarboxylate

A mixture of ethyl 1-(6-chloropyridin-3-yl)cyclopropanecarboxylate (69.8mg, 0.309 mmol) and pyrrolidine (250.0 μL, 3.0 mmol) in a sealed tubewas heated at 100° C. for 4 hours. Then the excess pyrrolidine in themixture was removed under reduced pressure. The residue was purified byflash chromatography column to afford ethyl1-(6-pyrrolidin-1-ylpyridin-3-yl)cyclopropanecarboxylate.

Step 2:(1R)-1′-([1-(6-pyrrolidin-1-ylpyridin-3-yl)cyclopropyl]carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

The above material of ethyl1-(6-pyrrolidin-1-ylpyridin-3-yl)cyclopropanecarboxylate was treatedwith LiOH in methanol to afford the corresponding acid, which was thencoupled with 3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-onedihydrochloride using procedures analogous to those for example 96 toafford(1R)-1′-{[1′-(6-pyrrolidin-1-ylpyridin-3-yl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one.MS (ESI): (M+H)⁺=405.1

Example 101(1R)-1′-{[1-(6-Pyrrolidin-1-ylpyridin-3-yl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared using procedures analogous to those forexample 96. The yield: 0.54%. MS (ESI): (M+H)⁺=404.2

Example 102(1R)-1′-({1-[4-(2-Oxo-1,3-oxazolidin-3-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-oneStep 1: tert-Butyl1-[4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]cyclopropanecarboxylate.

A mixture of tert-butyl 1-(4-bromophenyl)cyclopropanecarboxylate (297.2mg, 1.0 mmol), 2-oxo-1,3-oxazolidine (1.2 mmol), copper(I) iodide (20.0mg, 0.1 mmol), (trans)-cyclohexane-1,2-diamine (22.8 mg, 0.2 mmol) andpotassium carbonate (300.0 mg, 2.17 mmol) was deaerated under vacuum andthen charged with nitrogen. To the mixture was added toluene (2.0 mL).The resulting mixture was heated at 100° C. for overnight. Then ethylacetate (10 mL) was added to the mixture. The resulting mixture wasfiltered through a pad of celite, and the solid was washed withadditional ethyl acetate. The filtrate was concentrated. The residue waspurified by flash chromatography with ethyl acetate/hexane to affordtert-butyl1-[4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]cyclopropanecarboxylate.

Step 2:(1R)-1′-({1-[4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

t-Butyl 1-[4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]cyclopropanecarboxylatewas converted to the final compound using the procedures analogous tothose for example 96. MS (ESI): (M+H)⁺=419.1

Example 103(1R)-1′-({4-[4-(2-Oxopyrrolidin-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-oneStep A:tert-Butyl-[4-(2-oxopyrrolidin-1-yl)phenyl]cyclopropanecarboxylate

A mixture of tert-butyl 1-(4-bromophenyl)cyclopropanecarboxylate (297.2mg, 1.0 mmol), 2-oxo-pyrrolidine (1.2 mmol), copper(I) iodide (20.0 mg,0.1 mmol), (trans)-cyclohexane-1,2-diamine (22.8 mg, 0.2 mmol) andpotassium carbonate (300.0 mg, 2.17 mmol) was deaerated under vacuum andthen charged with nitrogen. To the mixture was added toluene (2.0 mL).The resulting mixture was heated at 100° C. for overnight. Then ethylacetate (10 mL) was added to the mixture. The resulting mixture wasfiltered through a pad of celite, and the solid was washed withadditional ethyl acetate. The filtrate was concentrated. The residue waspurified by flash chromatography with ethyl acetate/hexane to affordtert-butyl 1-[4-(2-oxo-pyrrolidin-1-yl)phenyl]cyclopropanecarboxylate.

Step B:(1R)-1′-({1-[4-(2-oxopyrrolidin-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

tert-Butyl 1-[4-(2-oxopyrrolidin-1-yl)phenyl]cyclopropanecarboxylate wasconverted to the final compound using the procedures analogous to thosefor example 96. MS (ESI): (M+H)⁺=425.1

Example 1041′-({1-[4-(2-Phenylethoxy)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-oneStep 1

1-(4-Hydroxyphenyl)cyclopropane-carboxylic acid (0.19 g, 1.0 mmol),benzotriazol-1-yloxytris(dimethylamino) phosphonium hexafluorophosphate(0.24 g, 1.0 mmol) and N,N-dimethylformamide (1.5 ml) were mixed withstirring at room temperature for ten minutes. To the mixture, withstirring, was added 3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-onedihydrochloride (0.47 g, 1.0 mmol), followed byN,N-Diisopropylethylamine (0.55 ml, 3.2 mmol). The resulting mixture wasstirred at r.t. overnight. Then the reaction was quenched with water,and the reaction mixture was extracted with ethyl acetate. The extractwas washed with saturated KH₂PO₄ solution (×2), water (×1), saturatedNaHCO₃ solution (×2), water (×1) and brine (×1) successively; then driedover Na₂SO₄; and then filtered. The filtrate was concentrated. Theresidue was further dried under high vacuum, and the desired product wasobtained (0.43 g).

Step 2

A mixture of1′-{[1-(4-hydroxyphenyl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one(15 mg, purity: 80%, 0.034 mmol), (2-iodoethyl)-benzene (12 mg, 0.051mmol), and tetra-n-butylammonium iodide (1 mg, 0.003 mmol), and CesiumCarbonate (28 mg, 0.086 mmol) in Dimethyl sulfoxide (0.3 ml) was stirredat r.t. overnight. Then the desired product was obtained from themixture by prep-HPLC (0.24 mg). LCMS: m/z 455.1 (M+H)⁺; 477.0 (M+Na)⁺.

Example 1051′-[(1-{4-[(1-Methylcyclopropyl)methoxy]phenyl}cyclopropyl)-carbonyl]-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

1′-{[1-(4-Hydroxyphenyl)cyclopropyl]-carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one(8.2 mg, 0.023 mmol), triethylamine (3.6 ul, 0.026 mmol),triphenylphosphine (15 mg, 0.056 mmol), and diisopropyl azodicarboxylate(11 ul, 0.056 mmol) were mixed in tetrahydrofuran (0.2 ml) at roomtemperature for 10 minutes. To the mixture, with stirring, was added(1-methylcyclopropyl)methanol (4.8 mg, 0.056 mmol). The resultingmixture then was stirred at room temperature overnight. The desiredproduct was obtained from the mixture by prep-HPLC (5.8 mg, 59%). LCMS:m/z 419.1 (M+H)⁺.

Example 1061′-[(1-{4-[(2-Fluorobenzyl)oxy]phenyl}cyclopropyl)carbonyl]-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared using similar procedures to those describedin example 104. LCMS: m/z 459.2 (M+H)⁺; 481.3 (M+Na)⁺.

Example 1071′-({1-[4-(Quinolin-2-ylmethoxy)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared using similar procedures to those describedin example 104. LCMS: m/z 492.3 (M+H)⁺; 514.2 (M+Na)⁺.

Example 1081′-[(1-{4-[(3-Fluorobenzyl)oxy]phenyl}cyclopropyl)carbonyl]-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared using similar procedures to those describedin example 104. LCMS: m/z 459.2 (M+H)⁺; 481.1 (M+Na)⁺.

Example 1091′-({1-[4-(1,3-Benzothiazol-2-ylmethoxy)phenyl]cyclopropyl}-carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared using similar procedures to those describedin example 105. LCMS: m/z 498.2 (M+H)⁺; 520.1 (M+Na)⁺.

Example 1101′-{[1-(4-{[3,5-Bis(trifluoromethyl)benzyl]oxy}phenyl)-cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared using similar procedures to those describedin example 104. LCMS: m/z 577.2 (M+H)⁺; 599.2 (M+Na)⁺.

Example 1111′-[(1-{4-[2-(4-Fluorophenyl)ethoxy]phenyl}cyclopropyl)-carbonyl]-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared using similar procedures to those describedin example 104. LCMS: m/z 473.2 (M+H)⁺; 495.1 (M+Na)⁺.

Example 1124-[(4-{1-[(3-Oxo-1′H,3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-1′-yl)carbonyl]cyclopropyl}phenoxy)methyl]benzonitrile

This compound was prepared using similar procedures to those describedin example 104. LCMS: m/z 466.2 (M+H)⁺; 488.2 (M+Na)⁺.

Example 1131′-{[1-(4-Phenoxyphenyl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

A mixture of 1-(4-phenoxyphenyl)cyclopropanecarboxylic acid (15 mg,0.059 mmol), 3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-onedihydrochloride (16 mg, 0.059 mmol),benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(27.4 mg, 0.062 mmol), and N,N-diisopropylethylamine (36 ul, 0.21 mmol)in N,N-dimethylformamide (1 ml) was stirred at room temperature for 4hours. The desired product then was obtained from the mixture byprep-HPLC (6.2 mg, 25%). LCMS: m/z 427.1 (M+H)⁺; 449.1 (M+Na)⁺.

Example 114(1R)-1′-({1-[4-(Pyridin-4-ylmethoxy)phenyl]cyclopropyl}-carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one:Step 1

A mixture of 1-(4-hydroxyphenyl)cyclopropanecarboxylic acid (0.20 g, 1.1mmol),[(1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonicacid-(1R)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one salt (0.47 g, 1.1mmol), Benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (0.55 g, 1.2 mmol), and N,N-diisopropylethylamine(0.49 ml, 2.8 mmol) in methylene chloride (3 ml) was stirred at r.t.overnight. Then the reaction was quenched with water, and the reactionmixture was extracted with ethyl acetate. The extract was washed with 1NHCl aqueous solution (×2), water and brine successively; then dried overNa₂SO₄; and then filtered. The filtrate was concentrated to afford thedesired product (0.35 g, yield: 89%).

Step 2

A mixture of(1R)-1′-{[1-(4-hydroxyphenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one(15 mg, 0.043 mmol), 4-(bromomethyl)pyridine hydrobromide (13 mg, 0.052mmol), Cesium Carbonate (56 mg, 0.17 mmol), and Tetra-n-butylammoniumiodide (1.6 mg, 0.004 mmol) in Dimethyl sulfoxide (0.3 ml) was stirredat r.t. overnight. Then the desired product was obtained from themixture by prep-HPLC (10.0 mg, yield: 53%). LCMS: m/z 441.1 (M+H) %463.1 (M+Na)⁺.

Example 115(1R)-1′-({1-[4-(Pyridin-2-ylmethoxy)phenyl]cyclopropyl}-carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared using similar procedures to those describedin example 114. LCMS: m/z 441.2 (M+H)⁺; 463.3 (M+Na)⁺.

Example 116(1R)-1′-{[1-(4-pyridin-4-ylphenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-oneStep 1

A mixture of 1-(4-bromophenyl)cyclopropanecarboxylic acid (1.0 g, 4.1mmol),[(1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonicacid-(1R)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (1:1) salt (1.7g, 4.1 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (1.8 g, 4.1 mmol), and N,N-diisopropylethylamine(1.8 ml, 10 mmol) in methylene chloride (7 ml) was stirred at roomtemperature for 4 hours. Then the mixture was diluted with ethylacetate. The resulting solution was washed with saturated KH₂PO₄solution (×2), water, saturated NaHCO₃ solution, water and brinesuccessively; then dried over Na₂SO₄; and then filtered. The filtratewas concentrated to afford the product (1.5 g).

Step 2

A mixture of(1R)-1′-{[1-(4-bromophenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one(25 mg, 0.061 mmol), 4-(tributylstannyl)pyridine (24 mg, 0.067 mmol),tris(dibenzylideneacetone)dipalladium(0) (3 mg, 0.003 mmol),tri-tert-butylphosphine (1.5 mg, 0.007 mmol), and potassium fluoride (12mg, 0.20 mmol) in tetrahydrofuran (0.3 ml) was microwave irradiated at90° C. for 15 minutes. Then the desired product was obtained from themixture by prep-HPLC (3.2 mg, yield: 13%). LCMS: m/z 411.1 (M+H)⁺; 433.0(M+Na)⁺.

Example 117(1R)-1′-{[1-(4-cyclopropylphenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared using similar procedures to those describedin example 116. LCMS: m/z 374.1 (M+H)⁺; 396.1 (M+Na)⁺.

Example 118(1R)-1′-{[1-(2-Fluoro-4-pyridin-2-ylphenyl)cyclopropyl]-carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-oneStep 1

A mixture of 1-(4-chloro-2-fluorophenyl)cyclopropanecarboxylic acid(0.15 g, 0.7 mmol),[(1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonicacid-(1R)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (1:1) salt (0.29g, 0.7 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (0.34 g, 0.77 mmol), and N,N-diisopropylethylamine(0.43 ml, 2.4 mmol) in N,N-dimethylformamide (2.0 ml) was stirred atroom temperature overnight. The mixture then was diluted with ethylacetate. The resulting solution was washed with saturated NaHCO₃solution, water, 1N HCl solution, water and brine successively; thendried over Na₂SO₄; and then filtered. The filtrate was concentrated toafford the desired product (275 mg).

Step 2

A mixture of(1R)-1′-{[1-(4-chloro-2-fluorophenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one(20 mg, purity: 80%, 0.04 mmol), 2-(tributylstannyl)-pyridine (17 mg,0.046 mmol), Tris(dibenzylideneacetone)dipalladium(0) (2 mg, 0.002mmol), tri-tert-butylphosphine (0.8 mg, 0.004 mmol), and cesiumcarbonate (16 mg, 0.05 mmol) in 1,4-dioxane (0.5 ml) was microwaveirradiated at 100° C. for 30 minutes. The product was obtained from themixture by prep-HPLC. LCMS: m/z 429.2 (M+H)⁺; 451.1 (M+Na)⁺.

Example 119(1R)-1′-[(1-{4-[(E)-2-(4-Methylphenyl)vinyl]phenyl}-cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

A mixture of(1R)-1′-{[1-(4-bromophenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one(25 mg, 0.061 mmol), [(E)-2-(4-methylphenyl)vinyl]boronic acid (11 mg,0.067 mmol), tri-tert-butylphosphine (1.5 mg, 0.007 mmol),tris(dibenzylideneacetone)dipalladium(0) (3 mg, 0.003 mmol), potassiumfluoride (12 mg, 0.2 mmol) in tetrahydrofuran (0.4 ml) was microwaveirradiated at 90° C. for 20 minutes. The desired product was obtainedfrom the mixture by prep-HPLC (13.7 mg, yield: 50%). LCMS: m/z 450.2(M+H)*; 472.2 (M+Na)⁺.

Example 120(1R)-1′-({1-[4-(2-Pyridin-2-ylethoxy)phenyl]cyclopropyl}-carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

(1R)-1′-{[1-(4-Hydroxyphenyl)-cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one(15 mg, 0.043 mmol), diisopropyl azodicarboxylate (20 ul, 0.10 mmol),and triphenylphosphine (24 ul, 0.10 mmol) were mixed in tetrahydrofuran(0.2 ml) at room temperature for 5 minutes. To the mixture, withstirring, was added 2-(2-pyridyl)ethanol (13 mg, 0.10 mmol). Theresulting mixture then was stirred at room temperature overnight. Thenthe desired product was obtained from the mixture by prep-HPLC (6.4 mg,yield: 33%), LCMS: m/z 455.2 (M+H)⁺.

Example 1211′-({1-[4-(2-Pyridin-2-ylethoxy)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared using similar procedures to those describedin example 105. LCMS: m/z

Example 122(1R)-1′-[(1-{4-[(E)-2-Pyridin-4-ylvinyl]phenyl}cyclopropyl)-carbonyl]-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

A mixture of POPd1 catalyst (CombiPhos Catalysts, Inc) (2 mg),(1R)-1′-{[1-(4-bromophenyl)cyclopropyl]-carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one(15 mg, 0.036 mmol), 4-vinylpyridine (19 mg, 0.18 mmol), potassiumcarbonate (5.5 mg, 0.04 mmol) in N,N-dimethylformamide (0.3 ml) wasmicrowave irradiated at 135° C. for 30 minutes. Then the desired productwas obtained from the mixture by prep-HPLC followed by chiral HPLC (13mg, 82%). LCMS: m/z 437.2 (M+H)⁺; 459.2 (M+Na)⁺.

Example 123(1R)-1′-({1-[4-(3,5-Dimethylisoxazol-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-oneStep 1a: Synthesis of 1-(4-bromophenyl)cyclopropanecarboxylic acid

2-(4-Bromophenyl)acetonitrile (10.0 g, 0.0510 mol),1-bromo-2-chloro-ethane (5.5 mL, 0.066 mol) and benzyltriethylammoniumchloride (200 mg, 0.001 mol) were added to a flask with vigorouslystirring, then 19.4 M of sodium hydroxide in water (18.4 mL) was addeddropwise. The mixture was stirred at 4° C. overnight. The reactionmixture was diluted with water and extract with ethyl acetate. Theorganic phase was washed with 1N HCl aqueous solution and brinesuccessively; then dried with MgSO₄; and then concentrate.

To a mixture of the above residue (6.0 g, 0.027 mol) and 19.4 M ofsodium hydroxide in water (5.6 mL) was added 1,2-ethanediol (60 mL, 1mol). The resulting mixture was refluxed at 120 Celsius for 20 hours.The reaction mixture was cooled down to r.t., then poured into water andthe resulting mixture was extracted with ether. The aqueous phase wasacidified with HCl aqueous solution and extracted with ethyl acetate.Then the ethyl acetate phase was washed with brine, then dried withMgSO₄, and then concentrated to afford the desired compound. MS (ESI):241.0.0 (M+H⁺)

Step 1b: Synthesis of(1R)-1′-{[1-(4-bromophenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

To a solution of 1-(4-bromophenyl)cyclopropanecarboxylic acid (1.0 g,0.0041 mol) in N,N-dimethylformamide (5 mL, 0.06 mol) was added[(1S,4S)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonicacid-(1R)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (1:1) (1.75 g,0.00415 mol). The solution was cooled to 0° C., andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(2.02 g, 0.00456 mol) was added. After stirring for about 3 minutes,N,N-diisopropylethylamine (2.17 mL, 0.0124 mol) was added to themixture. The resulting solution was stirred at 0° C. for 20 minutes,then at r.t. overnight.

Then the solution was poured into a saturated NaHCO₃ aqueous solution,and the mixture was extracted with ethyl acetate. The organic phase waswashed with saturated NaHCO₃ aqueous solution (×3), water and brinesuccessively; then dried with MgSO₄; and then concentrate. The residuewas flash chromatographed on silica gel column with 50% AcOEt in Hexanesto afford the desired compound. MS (EST): 414.0.0 (M+412.00 (M−H⁺).

Step 1c:(1R)-1′-({1-[4-(3,5-dimethylisoxazol-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

To a solution of(1R)-1′-{[1-(4-bromophenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one(20 mg, 0.00005 mol) in tetrahydrofuran (1.0 mL, 0.012 mol) were added3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole(11.9 mg, 0.0000534 mol), tris(dibenzylideneacetone)dipalladium(0) (0.2mg, 0.0000002 mol), tri-tert-butylphosphine (0.12 mg, 5.8E-7 mol) andpotassium fluoride (9.3 mg, 0.00016 mol), and the resulting mixture washeated at 150 Celsius under microwave for 50 minutes. The mixture thenwas cooled down to r.t. and filtered. The filtrate was diluted withmethanol, and the desired compound was obtained by revised phaseprep-HPLC. MS (ESI): 429.2 (M+H⁺).

Example 124(1R)-1′-({1-[4-(1-Methyl-1H-pyrazol-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared using procedures analogous to step 1c inexample 123. MS (ESI): 414.1 (M+H⁺)

Example 125(1R)-1′-({1-[4′-(Methylsulfonyl)biphenyl-4-yl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared using procedures analogous to step 1c inexample 123. MS (ESI): 488.1 (M+

Example 1261′-({1-[4-(3-Methyl-1H-pyrazol-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

To a solution of1′-{[1-(4-bromophenyl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one(30 mg, 0.00007 mol), 3-methyl-1H-pyrazole (7.15 mg, 0.0000871 mol) intoluene (0.5 mL, 0.005 mol) and N,N-dimethylformamide (0.5 mL, 0.006mol) were added (1S,2S)—N,N′-dimethylcyclohexane-1,2-diamine (2.1 mg,0.000014 mol), copper(I) iodide (1 mg, 0.000007 mol), and potassiumcarbonate (21.1 mg, 0.000152 mol). The mixture was heated at 150 Celsiusunder microwave for 60 minutes. Then the mixture was cooled down to r.t.and filtered. The filtrate was diluted with methanol, and the desiredcompound was obtained by reversed phase prep-HPLC. MS (ESI): 415.1 (M+

Example 1271′-[(1-{4-[3-(Trifluoromethyl)-1H-pyrazol-1-yl]phenyl}cyclopropyl)carbonyl]-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared using procedures analogous to those inexample 126. MS (ESI): 469.1 (M+H⁺)

Example 1281′-({1-[4-(4-Methyl-1H-pyrazol-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared using procedures analogous to those inexample 126. MS (ESI): 415.1 (M+

Example 129(1R)-1′-({1-[4-(2H-Indazol-2-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

To a solution of1′-{[1-(4-bromophenyl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one(30 mg, 0.00007 mol), 1H-Indazole (10.3 mg, 0.0000871 mol) in toluene (1mL, 0.01 mol) were added (1S,2S)—N,N′-dimethylcyclohexane-1,2-diamine(2.1 mg, 0.000014 mol), copper(I) iodide (1 mg, 0.000007 mol), andpotassium phosphate (32.4 mg, 0.000152 mol) in a sealed vial. Themixture was microwaved at 150 Celsius for 60 minutes. Then the mixturewas cooled down to r.t. and filtered. The filtrate was diluted withmethanol, and the desired compound was obtained by revised phaseprep-HPLC. MS (ESI): 451.1 (M+H⁺). The enantiomers were separated bychiral HPLC.

Example 130(1R)-1′-({1-[4-(1H-benzimidazol-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

To a solution of1′-{[1-(4-bromophenyl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one(30 mg, 0.00007 mol), 1H-Imidazole, 2-methyl-(7.15 mg, 0.0000871 mol) inN,N-dimethylformamide (1 mL, 0.01 mol) were added(1S,2S)—N,N′-dimethylcyclohexane-1,2-diamine (2.1 mg, 0.000014 mol),copper(I) iodide (1 mg, 0.000007 mol), and cesium carbonate (49.7 mg,0.000152 mol). The mixture was microwaved at 200 Celsius for 60 minutes.Then the mixture was cooled down to r.t. and filtered. The filtrate wasadjusted to be acidic using TFA and stirred for 30 minutes, then dilutedwith methanol and purified by revised phase prep-HPLC followed by chiralHPLC to afford the desired compound. MS (ESI): 451.1 (M+H⁺).

Example 131(1R)-1′-({1-[4-(2-Methyl-1H-imidazol-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared using procedures analogous to those inexample 130. MS (ESI): 415.1 (M+H⁺)

Example 132(1R)-1′-({1-[4-(1H-1,2,4-triazol-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared using procedures analogous to those inexample 129. MS (ESI): 401.1 (M+H⁺)

Example 133(1R)-1′-({1-[4-(1-Hydroxycyclopentyl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-oneStep 1a: 1-[4-(1-hydroxycyclopentyl)phenyl]cyclopropanecarboxylic acid

A solution of 1-(4-bromophenyl)cyclopropanecarboxylic acid (600.0 mg,0.002489 mol) in tetrahydrofuran (20 mL, 0.2 mol) was cooled below −20Celsius under N₂ atmosphere, and 1.0 M of dibutylmagnesium in heptane(1.3 mL) was slowly added to the solution while maintaining thetemperature below −20 Celsius. Then n-butyllithium (2.5 M in hexane, 1.1mL) was slowly added to the slurry while maintaining the temperaturebelow −20 Celsius with effective stirring. After the mixture was stirredat −20 Celsius for 1 hour, a solution of cyclopentanone (0.264 mL,0.00299 mol) in THF (20.0 mL) was added to the mixture. Then afterstirring at −20 Celsius for 1 hour, the reaction was quenched withammonium chloride and the reaction mixture was extracted with ethylacetate. The organic phase was washed with brine, then dried overNa₂SO₄, and then filtered. The filtrate was concentrated. The residuewas flash chromatographed on silica gel column with 30% ethyl acetate inhexanes to afford the desired compound. MS (ESI): 229.1 (M−OH⁻), 269.1(M+Na⁺).

Step 1b:(1R)-1′-({1-[4-(1-hydroxycyclopentyl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared using procedures analogous to step 1b inexample 123. MS (ESI): 400.1 (M−OH⁻)

Example 134(1R)-1′-{[1-(4-Cyclopentylphenyl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-oneStep 1a: 1-(4-cyclopentylphenyl)cyclopropanecarboxylic acid

The mixture of 1-[4-(1-hydroxycyclopentyl)phenyl]cyclopropanecarboxylicacid (120 mg, 0.00049 mol), triethylsilane (389 μL, 0.00244 mol) and TFA0.3 mL was stirred at r.t. overnight. The mixture was concentrated toafford desired product. MS (ESI): 231.1 (M+

Step 1b:(1R)-1′-{[1-(4-cyclopentylphenyl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared using procedures analogous to step 1b inexample 123. MS (ESI): 403.1 (M+

Example 135 (1R)-1%({1-[4-(1-Hydroxycyclopentyl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared using procedures analogous to those inexample 133. MS (ESI): 401.1 (M−OH⁻)

Example 136(1R)-1′-({1-[4-(1-Hydroxycyclobutyl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared using procedures analogous to those inexample 133. MS (ESI): 404.3 (M+

Example 137(1R)-1′-({1-[4-(1-Hydroxycyclobutyl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared using procedures analogous to those inexample 133. MS (ESI): 387.2 (M−OH⁻), 405.2 (M+H⁺)

Example 138(1R)-1′-({1-[4-(Tetrahydro-2H-pyran-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared using procedures analogous to those inexample 134. MS (ESI): 419.1 (M+H⁺)

Example 139(1R)-1′-{[1-(4-Cyclobutylphenyl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared using procedures analogous to those inexample 134. MS (ESI): 389.0 (M+H⁺).

Example 140(1R)-1′-({1-[4-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared using procedures analogous to those inexample 133. MS (ESI): 434.0 (M+H⁺)

Example 141(1R)-1′-({1-[4-(4-Hydroxytetrahydro-2H-pyran-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared using procedures analogous to those inexample 133. MS (ESI): 417 (M−OH⁻), 435.0 (M+H⁺)

Example 142(1R)-1′-({1-[4-(2-Amino-1,3-thiazol-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-oneStep 1. Methyl 1-phenylcyclopropanecarboxylate

Methyl iodide (2.8 mL, 45.0 mmol) was added to a mixture of1-phenylcyclo-propanecarboxylic acid (4.9 g, 30.0 mmol) and potassiumcarbonate (8.3 g, 60.0 mmol) in DMF (50 mL) at room temperature and thereaction mixture was stirred for 1 h. Then the reaction mixture wasdiluted with diethyl ether. The resulting mixture was washed with water(×2) and brine successively, then dried and concentrated to afford thedesired product.

Step 2. Methyl 1-[4-(chloroacetyl)phenyl]cyclopropanecarboxylate

Aluminium trichloride (7.9 g, 60.0 mmol) was added in portions to amixture of methyl 1-phenylcyclopropanecarboxylate (3.5 g, 20.0 mmol) andchloroacetyl chloride (2.0 mL, 26.0 mmol) in carbon disulfide (40.0 mL)at 15-25° C. The reaction mixture was stirred for 2 hours at roomtemperature. Then the mixture was poured into concentrated HCl (10.0 mL)in ice (100 g). The resulting mixture was extracted with diethyl etherseveral times. The combined organic phase was washed with brine, thendried and concentrated. The crude product was purified by CombiFlashusing hexane/ethyl acetate.

Step 3. Methyl1-[4-(2-amino-1,3-thiazol-4-yl)phenyl]cyclopropanecarboxylate

A mixture of methyl 1-[4-(chloroacetyl)phenyl]cyclopropanecarboxylate(0.30 g, 1.2 mmol) and thiourea (0.18 g, 2.4 mmol) in ethanol (5.0 ml)was refluxed overnight. The reaction mixture was diluted with ethylacetate and washed with saturated NaHCO₃ and brine successively; thendried; and then concentrated. The residue was triturated with etherfollowed by filtration to afford the product. LC-MS: 275.1 (M+H)⁺.

Step 4. 1-[4-(2-Amino-1,3-thiazol-4-yl)phenyl]cyclopropanecarboxylicacid

Lithium hydroxide monohydrate (0.24 g, 5.8 mmol) was added to a mixtureof methyl 1-[4-(2-amino-1,3-thiazol-4-yl)phenyl]cyclopropanecarboxylate(0.2 g, 0.73 mmol) in THF (3.0 ml) and water (1.0 mL), and the resultingmixture was refluxed for 30 minutes. Then the reaction mixture wasconcentrated and the residue was adjusted to be acidic (pH==3) by 1N HClaqueous solution. The precipitate formed was filtered and washed withwater to afford the desired product. LC-MS: 261.0 (M+H)⁺.

Step 5

N,N-Diisopropylethylamine (50 μL, 0.3 mmol) was added to a mixture of1-[4-(2-amino-1,3-thiazol-4-yl)phenyl]cyclopropanecarboxylic acid (26.0mg, 0.1 mmol), (1S)-(+)-10-camphorsulfonicacid-3H-spiro-[2-benzofuran-1,3′-pyrrolidin]-3-one (1:1) (42.1 mg, 0.01mmol) and BOP (57.0 mg, 0.13 mmol) in DMF (0.5 mL) at room temperature,and the reaction mixture was stirred for about 5 hours (the completionof the reaction was determined by HPLC). The crude product was purifiedby prep-HPLC. LC-MS: 432.1 (M+H)⁺.

Example 143(1R)-1′-({1-[4-(2-Methyl-1,3-thiazol-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared using procedures analogous to those inexample 142. LC-MS: 431.1 (M+H)⁺.

Example 144(1R)-1′-({1-[4-(2-Ethyl-1,3-thiazol-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared using procedures analogous to those inexample 142. LC-MS: 445.2 (M+H)⁺.

Example 145(1R)-1′-({1-[4-(2-Amino-1,3-thiazol-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared using procedures analogous to those inexamples 142. LC-MS: 433.2 (M+H)⁺.

Example 146(1R)-1′-({1-[4-(2-Methyl-1,3-thiazol-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared using procedures analogous to those inexamples 142. LC-MS: 432.1 (M+H)⁺.

Example 147(1R)-1′-({1-[4-(1,3-Thiazol-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

Isoamyl nitrite (10.0 μL) was added to a solution of(1R)-1′-({1-[4-(2-amino-1,3-thiazol-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one(25.0 mg, 0.06 mmol) in 1,4-dioxane (1.0 mL), and the reaction mixturewas stirred at 80° C. for 2 hours. Then the solvent from the mixture wasremoved and the crude product was purified by prep-HPLC. LC-MS: 417.1(M+H)⁺.

Example 1484-(1-{[1-(4-Chlorophenyl)-3-(methoxymethoxy)cyclobutyl]carbonyl}pyrrolidin-3-yl)pyridineStep 1. 1-(4-chlorophenyl)-3-(methoxymethoxy)cyclobutanecarboxylic acid

A solution of1-(4-chlorophenyl)-3-(methoxymethoxy)cyclobutanecarbonitrile, KOH, andethylene glycol was heated to 198° C. for 6 h and then cooled to rt. Thereaction mixture was washed with ether (2×10 mL) and then the aqueoussolution was acidified (pH 3-4) with 4 M HCl (˜5 mL). The resultingaqueous mixture then was extracted with ether (2×20 mL) and the combinedorganic layers were dried over MgSO₄, filtered and concentrated toafford 0.6158 g of a brown oil (the reaction was monitored by theconsumption of the starting material by TLC). The identification of theproduct was confirmed by ¹H NMR and LCMS. LC-MS: 271.1 (M+H⁺).

Step 2

To a solution of1-(4-chlorophenyl)-3-(methoxymethoxy)cyclobutanecarboxylic acid inmethylene chloride was add DIEA, and the mixture was stirred for 10minutes. Then BOP was added and the mixture was stirred for 20 minutes.Then 4-pyrrolin-3-ylpyridine hydrochloride was added and the resultingmixture was stirred at room temperature overnight. The completion of thereaction was determined by LCMS. The reaction mixture then was poured into a saturated NaHCO₃ aqueous solution and the resulting mixture wasextract with CH₂Cl₂ (2×). The combined organic layers were dried overMgSO₄, then filtered and then concentrated in-vacuo. The crude productwas purified by flash column chromatography with MeOH/CH₂Cl₂ (1%, 3%,5%, 7%) to afford the desired product (24.1 mg). The identification ofthe product was confirmed by LCMS and ¹H NMR. LC/MS: 401.2 (M+H⁺).

Example 1493-(3-Chlorophenyl)-1-{[1-(4-chlorophenyl)-3-(methoxymethoxy)cyclobutyl]carbonyl}pyrrolidine

This compound was prepared using procedures analogous to those inexample 148. LC-MS: 435.1 (M+H)⁺.

Example 1501′-{[trans-1-(4-Chlorophenyl)-3-hydroxycyclobutyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-oneStep 1. trans-1-(4-Chlorophenyl)-3-hydroxycyclobutanecarboxylic acid

The corresponding aldehyde was dissolved in t-BuOH/THF/2-methylbut-2-eneand the mixture was stirred at room temperature. A solution of sodiumchlorite and sodium dihydrogen phosphate in water was added to themixture with stirring. The resulting mixture was stirred for 2 hours,then the volatiles were removed from the mixture. The residue wasacidified (to pH 2) with 1N HCl aqueous solution. The resulting mixturewas then extracted with EtOAc (3×). The combined organic phase was driedover MgSO₄, then filtered and concentrated to afford the desiredcarboxylic acid.

Step 2

This compound was prepared by using a procedure analogous to thatdescribed in example 4. LC/MS: 398.9 (M+H⁺).

Example 1511′-{[cis-1-(4-Chlorophenyl)-3-fluorocyclobutyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed in example 150 starting with the corresponding aldehyde.LC/MS: 400.1 (M+H⁺).

Example 1521′-{[cis-1-(4-Chlorophenyl)-3-fluorocyclobutyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidine]

This compound was prepared by using a procedure analogous to thatdescribed in example 150 starting with the corresponding aldehyde and3H-spiro[2-benzofuran-1,3′-pyrrolidine]hydrochloride. LC/MS: 386.1(M+H⁺).

Example 1531′-{[cis-1-(4-Chlorophenyl)-3-fluorocyclobutyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed in example 150 starting with the corresponding aldehyde and7H-spiro[furo[3,4-b]pyridine-5,3′-pyrrolidin]-7-one hydrochloride. Thecompound was purified by prep-HPLC. LC/MS: 401.1 (M+H⁺).

Example 1541′-{[cis-1-(4-Chlorophenyl)-3-fluorocyclobutyl]carbonyl}-7H-spiro[furo[3,4-b]pyridine-5,3′-pyrrolidin]-7-one

This compound was prepared by using a procedure analogous to thatdescribed in example 153. LC/MS: 401.1 (M+H⁺).

Example 1553-(1-{[1-(4-Chlorophenyl)cyclobutyl]carbonyl}pyrrolidin-3-yl)pyridine

This compound was prepared by using a procedure analogous to thatdescribed in example 1. LC/MS: 341.1 (M+H⁺).

Example 156(1R)-1′-{[1-(4-Chlorophenyl)cyclobutyl]carbonyl}-7H-spiro[furo[3,4-b]pyridine-5,3′-pyrrolidin]-7-one

To a solution of piperidine, 2,2,6,6-tetramethyl-(1.20 mL, 0.00713 mol)in tetrahydrofuran (30 mL, 0.4 mol) at −75 degrees celsius was added 2.5M of n-butyllithium in hexane (3.8 mL), and the mixture was stirred for15 minutes. Then a suspension of 2-pyridinecarboxylic acid (0.292 g,0.00238 mol) in THF was added and the resulting mixture was then stirredat −75 degrees celsius for 10 minutes and then at 0° C. for 1 hour. Asolution of 1-{[1-(4-chlorophenyl)cyclobutyl]carbonyl}pyrrolidin-3-one(550 mg, 0.0020 mol) in THF (2 mL) was added to the above mixture, andthe resulting mixture was stirred at 0 degrees celsius for 20 minutesand then at 0° C. 1 hour. The reaction mixture was acidified (to pH ˜1)using 6 M HCl aqueous solution and stirred at room temperatureovernight. The reaction mixture then was neutralized (to pH ˜7),extracted with AcOEt. The organic phase was washed with brine, thendried over MgSO₄, and concentrated. The crude product was purified byCombiflash and then the enantiomers were separated using a chiralcolumn. LC/MS: 383.1 (M+H⁺).

Example 157(1R)-1′-({1-[4-(1H-Indazol-1-yl)phenyl]cyclobutyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-oneStep 1.1′-{[1-(4-Bromophenyl)cyclobutyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed in example 90. LC/MS: 429.1 and 427.1 (M+H⁺).

Step 2

To a solution of1′-{[1-(4-bromophenyl)cyclobutyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one(30 mg, 0.00007 mol), and 1H-benzimidazole (0.010 g, 0.000087 mol) intoluene (0.5 mL, 0.005 mol) and N,N-dimethylformamide (0.5 mL, 0.006mol), were added (1S,2S)—N,N′-dimethylcyclohexane-1,2-diamine (2.1 mg,0.000014 mol), copper(I) iodide (1 mg, 0.000007 mol), and potassiumcarbonate (21.1 mg, 0.000152 mol), and the mixture was stirred at 120°C. overnight. The reaction mixture was then filtered and the filtratewas diluted with methanol. The product was purified using prep-HPLCfollowed by chiral HPLC. LC-MS: 465.2 (M+H)⁺.

Example 158(1R)-1′-[(1-{4-[3-(Trifluoromethyl)-1H-pyrazol-1-yl]phenyl}cyclobutyl)carbonyl]-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed in example 157, with the exception that the reaction washeated to 200° C. for 1 h in the microwave. LC/MS: 483.2 (M+H⁺).

Example 159(1R)-1′-({1-[4-(1H-Benzimidazol-1-yl)phenyl]cyclobutyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed in example 157. LC/MS: 465.2 (M+H⁺).

Example 160(1R)-1′-({1-[4-(2-Oxo-1,3-oxazolidin-3-yl)phenyl]cyclobutyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-oneStep 1.(1R)-1′-{[1-(4-bromophenyl)cyclobutyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed in example 116. LC/MS: 426.1 and 428.1 (M+H⁺).

Step 2

To a solution of(1R)-1′-{[1-(4-bromophenyl)cyclobutyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one(20.7 mg, 0.0000485 mol) and oxazolidin-2-one (12.7 mg, 0.000146 mol) infreshly distilled toluene (0.34 mL, 0.0032 mol), were addedtris(dibenzylidene acetone)dipalladium(0) (4.4 mg, 0.0000048 mol),tri-tert-butylphosphine (2.0 mg, 0.0000097 mol) and cesium carbonate(15.8 mg, 0.0000485 mol), and the mixture was heated to 50° C.overnight. The reaction mixture then was cooled to rt, filtered overcelite and concentrated under reduced pressure. The crude product waspurified by prep-HPLC. LC/MS (M+H) 433.2.

Example 161(1R)-1′-[(1-Pyridin-4-ylcyclobutyl)carbonyl]-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

Lithium hydroxide, monohydrate (0.013 g, 0.00031 mol) was added to asolution of ethyl 1-pyridin-4-ylcyclobutanecarboxylate (32 mg, 0.00016mol) in tetrahydrofuran (1.6 mL, 0.020 mol) and water (0.3 mL, 0.02mol). The mixture was stirred at room temperature until the reaction wascomplete. The mixture was acidified (to pH=5) with 4 M HCl (75 μl) andconcentrated to afford the carboxylic acid. Then[(1R,4S)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonicacid-(1R)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (1:1) (0.033 g,0.000078 mol) and (benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (0.041 g, 0.000078 mol) were added to the abovecrude product of the carboxylic acid, followed by 4-methylmorpholine(6.0 μL, 0.00055 mol). The reaction mixture was stirred at roomtemperature for 2 hours. The crude product was purified by prep-LCMS.LC/MS: 349.1 (M+H⁺).

Example 162(1R)-1′-{[1-(4-Pyridin-4-ylphenyl)cyclobutyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by a coupling procedure similar to thatdescribed in example 122 using 4-pyridinyl boronic acid and thecorresponding aryl bromide. LCMS: m/z 425.2 (M+H)⁺; 447.2 (M+Na)⁺.

Example 163N,N-Dimethyl-4-[5-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)pyridin-2-yl]piperazine-1-carboxamideStep 1. Ethyl 1-(6-chloropyridin-3-yl)cyclopropanecarboxylate

Sodium hydride (60% in mineral oil, 0.60 g, 15 mmol) was added to asolution of ethyl (6-chloropyridin-3-yl)acetate (1.0 g, 0.0050 mol) inN,N-dimethylformamide (10 mL, 0.1 mol) at rt under an atmosphere ofnitrogen. After 30 minutes, 1-bromo-2-chloro-ethane (0.84 mL, 0.010 mol)was added to the mixture at 0° C. The reaction mixture was stirred at35° C. for 4 hours and then at room temperature overnight. The mixturewas poured into a mixture of ice-water (50 ml) and EtOAc (50 ml) and theresulting mixture was acidified (to pH 2) by slow addition of 6 N HCl.The layers were separated and the organic layer was washed successivelywith water and brine, dried over MgSO₄ and concentrated. The residue waschromatographed by combiflash (ethyl acetate in hexanes: 80%, on silicagel) to afford the desired product. LC/MS: 226.0 and 228.0 (M+H⁺).

Step 2. tert-Butyl4-{5-[1-(ethoxycarbonyl)cyclopropyl]pyridin-2-yl}piperazine-1-carboxylate

A mixture of ethyl 1-(6-chloropyridin-3-yl)cyclopropanecarboxylate(225.7 mg, 0.001000 mol) and tert-butyl piperazine-1-carboxylate (3.0eq.) was heated at 130° C. for 6 h. After cooling, the mixture was flashchromatographed on a silica gel column to afford the desired product.LC/MS: 376.5 (M+H⁺).

Step 3. tert-Butyl4-[5-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)pyridin-2-yl]piperazine-1-carboxylate

To a solution of tert-Butyl4-{5-[1-(ethoxycarbonyl)cyclopropyl]pyridin-2-yl}-piperazine-1-carboxylate(113 mg, 0.000300 mol) in THF (1.00 mL) and water (1.00 mL) and methanol(1.00 mL) was added lithium hydroxide in water (2.00 M, 0.500 mL). Themixture was irradiated under microwave at 100° C. for 30 minutes, andthen was neutralized with 2 M HCl (0.50 mL). The mixture wasconcentrated and the residue was dissolved in DMF (3.0 mL). To thesolution were added[(1S)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonicacid-(1R)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (1:1) (164 mg,0.000390 mol), benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (146 mg, 0.000330 mol) and 4-methylmorpholine (160μL, 0.0014 mol). The resulting mixture was stirred at room temperaturefor 3 hours. The reaction mixture then was adjusted to be acidic (topH=2.0) with TFA and diluted with DMF (2.0 mL). The solution waspurified by prep-HPLC to give the desired product. LC/MS: 519.6 (M+H⁺).

Step 4.N,N-Dimethyl-4-[5(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)pyridin-2-yl]piperazine-1-carboxamide

To a solution of tert-Butyl4-[5-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)pyridin-2-yl]piperazine-1-carboxylate(10.4 mg, 0.0000200 mol) was added hydrogen chloride in 1,4-dioxane (4.0M, 20.0 μL), and the mixture was stirred at room temperature for 1 hour.The solvent of the mixture then was evaporated, and to the resultingresidue were added acetonitrile (1.00 mL, 0.0191 mol),N,N-diisopropylethylamine (20.0 μL, 0.000115 mol), andN,N-dimethylcarbamoyl chloride (4.8 μL, 0.000052 mol). The mixture wasstirred at room temperature for 30 minutes, then acidified (pH=2.0) withTFA, and then diluted with methanol (0.8 mL). The resulting solution waspurified by prep-HPLC to give the desired product. LC/MS: 490.6 (M+H⁺).

Example 164(1R)-1′-[(1-{6-[4-(Methylsulfonyl)piperazin-1-yl]pyridin-3-yl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by procedures analogous to those described inexample 163, with the exception that N,N-dimethylcarbamoyl chloride wassubstituted for methanesulfonyl chloride in step 4. LC/MS: 497.6 (M+H⁺).

Example 165(1R)-1′-[(1-{6-[4-(2-Fluorophenyl)piperazin-1-yl]pyridin-3-yl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by procedures analogous to those described inexample 163 (steps 1-3). LC/MS: 513.6 (M+H⁺).

Example 166(1R)-1′-({1-[6-(3,3-Difluoropyrrolidin-1-yl)pyridin-3-yl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by procedures analogous to those described inexample 163 (steps 1-3). LC/MS: 440.5 (M+H⁺).

Example 167(1R)-1′-[(1-{6-[(3S)-3-Hydroxypyrrolidin-1-yl]pyridin-3-yl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by procedures analogous to those described inexample 163 (steps 1-3). LC/MS: 420.5 (M+H⁺).

Example 168N-{(3R)-1-[5-(1-{[(1R)-3-Oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)pyridin-2-yl]pyrrolidin-3-yl}acetamide

This compound was prepared by using procedures analogous to thosedescribed in example 163 (steps 1-3). LC/MS: 461.5 (M+H⁺).

Example 169(1R)-1′-({1-[6-(1,3-Dihydro-2H-isoindol-2-yl)pyridin-3-yl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by procedures analogous to those described inexample 163 (steps 1-3). LC/MS: 452.5 (M+H⁺).

Example 170(1R)-1′-({1-[6-(3,4-Dihydroisoquinolin-2(1H)-yl)pyridin-3-yl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using procedures analogous to thosedescribed in example 163 (steps 1-3). LC/MS: 466.5 (M+H⁺).

Example 171(1R)-1′-{[1-(6-Morpholin-4-ylpyridin-3-yl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by procedures analogous to those described inexample 163 (steps 1-3). LC/MS: 420.1 (M+H⁺).

Example 172(1R)-1′-({1-[6-(4-Hydroxypiperidin-1-yl)pyridin-3-yl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by procedures analogous to those described inexample 163 (steps 1-3). LC/MS: 434.1 (M+H⁺).

Example 173N-{4-[5-(1-{[(1R)-3-Oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)pyridin-2-yl]phenyl}acetamideStep 1.(1R)-1′-{[1-(6-chloropyridin-3-yl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

4-Methylmorpholine (790 μL, 0.0072 mol) was added to a mixture of1-(6-chloropyridin-3-yl)cyclopropanecarboxylic acid (1.8 mmol, 0.0018mol), [(1R,4S)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonicacid-(1R)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (1:1) (760 mg,0.0018 mol) (prepared by methods described in example 96, steps 1-2),(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (984mg, 0.00189 mol), or benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (836 mg, 0.00189 mol) in N,N-dimethylformamide (10mL, 0.1 mol). The reaction mixture was stirred at room temperature for 2hours. The crude product was purified by prep-LCMS. LC/MS: 369.1 (M+H⁺).

Step 2

Sodium carbonate (12.7 mg, 0.000120 mol) in water (0.100 mL) was addedto a mixture of(1R)-1′-{[1-(6-chloropyridin-3-yl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one(22.1 mg, 0.0000600 mol), [4-(acetylamino)phenyl]boronic acid (10.7 mg,0.0000600 mol) and tetrakis(triphenylphosphine)palladium(0) (2.14 mg,1.86×10⁻⁶ mol) in toluene (200.00 μL, 0.0018776 mol) and ethanol (100.00μL, 0.0017127 mol). The resulting mixture was irradiated by microwave at120° C. for 15 minutes. Ethyl acetate (5 mL) was added and the resultingmixture was washed with water and brine successively. The organic layerwas dried over Na₂SO₄, then filtered, and then concentrated underreduced pressure. The residue was purified by Combiflash with ethylacetate/hexane to give the desired product. LC/MS: 468.5 (M+H⁺).

Example 174(1R)-1′-({1-[6-(2-Fluorophenyl)pyridin-3-yl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed in example 173. LC/MS: 429.1 (M+H⁺).

Example 175(1R)-1′-({1-[6-(1-Benzothien-3-yl)pyridin-3-yl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed in example 173. LC/MS: 467.6 (M+H⁺).

Example 176(1R)-1′-{[1-(2,3′-Bipyridin-5-yl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed in example 173. LC/MS: 412.5 (M+H⁺).

Example 177(1R)-1′-({1-[6-(1-Methyl-1H-indol-5-yl)pyridine-3-yl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed in example 96. LC/MS: 464.5 (M+H⁺).

Example 178(1R)-1′-[(1-{6-[3-(Trifluoromethoxy)phenyl]pyridine-3-yl]cyclopropyl)carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed in example 96. LC/MS: 495.5 (M+H⁺).

Example 179(1R)-1′-({1-[6-(3-Thienyl)pyridine-3-yl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed in example 96. LC/MS: 417.5 (M+H⁺).

Example 180(1R)-1′-[(1-{6-[3-(Trifluoromethyl)phenyl]pyridine-3-yl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed in example 96. LC/MS: 479.5 (M+H⁺).

Example 181(1R)-1′-({1-[6-(1-Methyl-1H-pyrazol-4-yl)pyridine-3-yl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed in example 96. LC/MS: 415.5 (M+H⁺).

Example 182(1R)-1′-{[1-(6-Chloropyridin-3-yl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed in example 96 (omitting step 3). LC/MS: 369.5 (M+H⁺).

Example 183(1R)-1′-({1-[6-(Benzyloxy)pyridin-3-yl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

The procedure that was outlined for the synthesis of example 96 wasfollowed with the exception that step 3 was omitted and replaced withthe following procedure:

Step 3 substitute. 1-[6-(benzyloxy)pyridin-3-yl]cyclopropanecarboxylicacid

A mixture of ethyl 1-(6-chloropyridin-3-yl)cyclopropanecarboxylate (45.1mg, 0.000200 mol), benzyl alcohol (0.50 mL, 0.0048 mol) and sodiumhydride (9.50 mg, 0.000238 mol) was irradiated by microwave at 150° C.for 15 minutes. After cooling, additional sodium hydride (9.5 mg) wasadded to the mixture. The mixture then was irradiated by microwave at150° C. for 15 minutes. Ethyl acetate (5 mL) was added and the resultingmixture was washed with water and brine successively. The organic layerwas dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified by Combiflash with ethylacetate/hexane to give the desired product.

Following the BOP coupling the desired product,(1R)-1′-({1-[6-(benzyloxy)pyridin-3-yl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one,was purified by prep-HPLC. LC/MS: 441.2 (MAT).

Example 184(1R)-1′-[(1-Quinolin-3-ylcyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by a procedure analogous to that used forexample 173 (step 1). LC/MS: 385.2 (M+H⁺).

Example 185(1R)-1′-({1-[6-(1-Methyl-1H-pyrazol-4-yl)pyridin-3-yl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed in example 96. LC/MS: 416.2 (M+H⁺).

Example 186(1R)-1′-({1-[6-(Benzyloxy)pyridin-3-yl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed in example 183. LC/MS: 442.2 (M+H⁺).

Example 187(1R)-1′-{[1-(6-Chloropyridin-3-yl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed in example 182. LC/MS: 370.5 (M+H⁺).

Example 188(1R)-1′-({1-[6-(3,4-Dihydroisoquinolin-2(1H)-yl)pyridin-3-yl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed in example 170. LC/MS: 467.2 (M+H⁺).

Example 189(1R)-1′-({1-[6-(1,3-Dihydro-2H-isoindol-2-yl)pyridin-3-yl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed in example 163. LC/MS: 453.2 (M+H⁺).

Example 190(1R)-1′-({1-[6-(3,3-Difluoropyrrolidin-1-yl)pyridin-3-yl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by a procedure analogous to the one describedin example 163 (steps 1-3). LC/MS: 441.2 (M+H⁺).

Example 191 (1R)-Isobutyl4-(5-{1-[(3-oxo-1′H,3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-1′-yl)carbonyl]cyclopropyl}pyridin-2-yl)piperazine-1-carboxylate

This compound was prepared by a procedure analogous to the one describedin example 163. LC/MS: 520.1 (M+H⁺).

Example 192(1R)-2-[4-(5-{1-[(3-Oxo-1′H,3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-1′-yl)carbonyl]cyclopropyl}pyridin-2-yl)piperazin-1-yl]benzonitrile

This compound was prepared by a procedure analogous to the one describedin example 163 (steps 1-3). LC/MS: 521.1 (M+H⁺).

Example 193(1R)-1′-[(1-{6-[4-(4-Fluorophenyl)piperazin-1-yl]pyridin-3-yl}cyclopropyl)carbonyl]-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by a procedure analogous to the one describedin example 163 (steps 1-3). LC/MS: 514.5 (M+H⁺).

Example 194(1R)-1′-[(1-{6-[3-(Trifluoromethyl)phenyl]pyridin-3-yl}cyclopropyl)carbonyl]-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by a procedure analogous to the one describedin example 96. LC/MS: 480.4 (M+H⁺).

Example 195(1R)-1′-[(1-{6-[3-(Trifluoromethoxy)phenyl]pyridin-3-yl}cyclopropyl)carbonyl]-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by a procedure analogous to the one describedin example 96. LC/MS: 496.1 (M+H⁺).

Example 196(1R)-4-(5-{1-[(3-Oxo-1′H,3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-1′-yl)carbonyl]cyclopropyl}pyridin-2-yl)benzonitrile

This compound was prepared by a procedure analogous to the one describedin example 173. LC/MS: 437.2 (M+H⁺).

Example 197(1R)-1′-({1-[6-(3-Chloro-4-fluorophenyl)pyridin-3-yl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by a procedure analogous to the one describedin example 173. LC/MS: 464.1 (M+H⁺).

Example 198(1R)-1′-[(1-{6-[4-(Methoxymethyl)phenyl]pyridin-3-yl]cyclopropyl)carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by a procedure analogous to the one describedin example 173. LC/MS: 456.2 (M+H⁺).

Example 199(1R)—N-[3-(5-{1-[(3-Oxo-1′H,3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-1′-yl)carbonyl]cyclopropyl}pyridin-2-yl)phenyl]acetamide

This compound was prepared by a procedure analogous to the one describedin example 173. LC/MS: 469.2 (M+H⁺).

Example 200(1R)-4-(5-{1-[(3-Oxo-1′H,3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-1′-yl)carbonyl]cyclopropyl}pyridin-2-yl)benzamide

This compound was prepared by a procedure analogous to the one describedin example 173. LC/MS: 455.2 (M+H⁺).

Example 201(1R)-1′-[(1-{6-[4-(Methylsulfonyl)phenyl]pyridin-3-yl}cyclopropyl)carbonyl]-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by a procedure analogous to the one describedin example 173. LC/MS: 490.1 (M+H⁺).

Example 202(1R)-1′-({1-[6-(1-Methyl-1H-indol-5-yl)pyridin-3-yl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by a procedure analogous to the one describedin example 96. LC/MS: 465.2 (M+H⁺).

Example 203(1R)-1′-({1-[6-(1-Benzothien-5-yl)pyridin-3-yl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by a procedure analogous to the one describedin example 96. LC/MS: 468.2 (M+H⁺).

Example 204(1R)-1′-{[1-(6-Quinolin-3-ylpyridin-3-yl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by a procedure analogous to the one describedin example 96. LC/MS: 463.2 (M+H⁺).

Example 205(1R)-1′-({1-[6-(3-Thienyl)pyridin-3-yl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by a procedure analogous to the one describedin example 96. LC/MS: 418.2 (M+H⁺).

Example 206(1R)-1′-({1-[4-(2-Oxo-2,3-dihydro-1H-indol-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by a procedure analogous to the one describedin example 129. LC/MS: 466.2 (M+H⁺).

Example 207(1R)-1′-({1-[4-(3-Methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-oneStep 1.1′-({1-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by a procedure analogous to the one describedin example 129. LC/MS: 467.2 (M+H⁺).

Step 2

To a solution of(1R)-1′-({1-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one(50 mg, 0.0001 mol) in dimethyl sulfoxide (1 mL, 0.01 mol) were addedpotassium carbonate (16.3 mg, 0.000118 mol) and methyl iodide (6.67 μL,0.000107 mol), and the mixture was stirred at room temperature for. 2hours. The crude product was purified by prep-HPLC.

Example 208(1R)-4-{1-[(3-Oxo-1′H,3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-1′-yl)carbonyl]cyclopropyl}benzonitrileStep 1. Methyl 1-(4-cyanophenyl)cyclopropanecarboxylate

A degassed mixture of methyl 1-(4-chlorophenyl)cyclopropanecarboxylate(4.748 g, 0.02254 mol), zinc cyanide (2.701 g, 0.02254 mol),bis(tri-t-butylphosphine)palladium (705 mg, 0.00135 mol) and zinc (265mg, 0.00406 mol) powder in anhydrous N-methylpyrrolidinone (50.0 mL,0.518 mol) was heated at 150° C. for 18 hours. The completion of thereaction is determined by LCMS and TLC. The reaction mixture was cooledto it, diluted with EtOAc, filtered through a pad of celite and thesolid was washed with EtOAc. The filtrate was washed with 2 N NH₄OH (100mL) and brine successively, dried over magnesium sulfate, filtered andconcentrated in vacuo. The residue was purified by Combiflash with 2-15%EtOAc/hexanes to give the product as a colorless oil (3.434 g, 76% inyield). LC/MS: (M+H)=202.1.

Step 2

The above compound was subjected to the analogous hydrolysis and amidecoupling reaction described in step 3 of example 163. LC/MS: 360.1(M+H⁺).

Example 2094-{1-[(3-Oxo-1′H,3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-1′-yl)carbonyl]cyclopropyl}benzenecarbothioamide

To a microwave vial were added4-{1-[(3-oxo-1′H,3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-1′-yl)carbonyl]cyclopropyl}benzonitrile(0.6085 g, 0.001693 mol), ammonium sulfide in water (7.34 M, 0.461 mL)and methanol (10.00 mL, 0.2469 mol). The resulting solution wasmicrowave irradiated at 100° C. for 30 minutes. The reaction wasquenched with 40 mL water, and yellow solid precipitated from thereaction mixture. The precipitated yellow solid was collected byfiltration. The filtrate was extracted with ethyl acetate (×3). Thecombined organic phase was washed with brine, dried over magnesiumsulfate, filtered and concentrated. No product was present in theorganic layer or aqueous layer. The precipitated yellow solid wasidentified as the desired product by ¹H NMR. No purification wasrequired. LC/MS: 394.1 (M+H⁺).

Example 210(1R)-1′-[(1-{4-[1-(Methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}cyclopropyl)carbonyl]-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-oneStep 1. 1-(4-bromophenyl)cyclopropanecarboxylic acid

Sodium hydroxide (50% aqueous solution, 60.0 g, 1.03 mol) was added to amixture of 4-bromobenzeneacetonitrile (19.6 g, 0.100 mol),benzyltriethylammonium chloride (1.8 g, 0.0079 mol), and1-bromo-2-chloro-ethane (30.0 g, 0.209 mol) at 50° C. for 5 hours.1,2-Ethanediol (200.0 mL, 3.588 mol) was added to the mixture and theresulting mixture was heated at 100° C. overnight. The mixture waspoured into ice-water (30 mL) and was extracted with ethyl ether (2×10mL). The aqueous phase was acidified (to pH=2) with 1N HCl and wasextracted with ethyl acetate (4×15 mL). The combined organic phases werewashed with brine (10 mL), dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. The residue was used in next step reactionwithout further purification.

Step 2.1-{4-[1-(tert-butoxycarbonyl)-4-hydroxypiperidin-4-yl]phenyl}cyclopropanecarboxylicacid

A solution of 1-(4-bromophenyl)cyclopropanecarboxylic acid (1000.0 mg,0.0041480 mol) in tetrahydrofuran (30 mL, 0.4 mol) was cooled below −20°C. under a N₂ atmosphere and dibutylmagnesium in heptane (1.0 M, 2.2 mL)was slowly added to the solution while the reaction temperature wasmaintained below −20° C. Then 2.5 M of n-butyllithium in hexane (1.8 mL)was slowly added to the mixture below −20° C. under effective stirring.After stirring below −20° C. for 1 h, a solution of tert-butyl4-oxo-1-piperidinecarboxylate (0.909 g, 0.00456 mol) in THF (20.0 mL)was added to the mixture below −20° C. After stirring below −20° C. for1 h, the reaction was quenched with ammonium chloride. The product wasextracted with EtOAc and the combined extract was washed with brine,dried over Na₂SO₄, and filtered. The filtrate was concentrated and thenpurified by Combiflash, eluting with 5% methanol in methylene chloride.

Step 3. tert-butyl4-hydroxy-4-(4-{1-[(3-oxo-1′H,3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-1′-yl)carbonyl]cyclopropyl}phenyl)piperidine-1-carboxylate

To a solution of1-{4-[1-(tert-butoxycarbonyl)-4-hydroxypiperidin-4-yl]phenyl}cyclopropanecarboxylicacid (230 mg, 0.00064 mol) in methylene chloride (2 mL, 0.03 mol) wasadded (1R)-3-H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-onedihydrochloride (184 mg, 0.000700 mol). The solution was cooled to 0°C., prior to the addition of BOP. The solution was stirred for 3 minutesand then DIEA was added. Stirring was continued at 0° C. for 20 minutesand then the reaction mixture was allowed to gradually warm to roomtemperature while stirring overnight. The crude product was purified byCombiflash eluting with 10% methanol in methylene chloride. LC/MS: 534.4(M+H⁺).

Step 4.1′-({1-[4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

To a solution of tert-butyl(1R)-4-hydroxy-4-(4-{1-[(3-oxo-1′H,3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-1′-yl)carbonyl]cyclopropyl}phenyl)piperidine-1-carboxylate(140 mg, 0.00026 mol) in methanol (1 mL, 0.02 mol) was added hydrogenchloride in 1,4-dioxane (4 M, 0.9 mL) and the resulting solution wasstirred at room temperature for 4 hours. The reaction mixture was thenconcentrated and TFA (2 mL) was added and the solution was stirred atroom temperature overnight. The solvent was removed to afford thedesired product. LC/MS: 416.2 (M+H⁺). Step 5.

To a solution of(1R)-1′-({1-[4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one(22 mg, 0.000053 mol) in acetonitrile (0.5 mL, 0.01 mol) were addedtriethylamine (16.8 μL, 0.000120 mol) and methane sulfonyl chloride. Thereaction mixture was stirred at room temperature overnight. The crudeproduct was purified by prep-HPLC. LC/MS: 494.2 (M+H⁺).

Example 211(1R)-1′-[(1-{4-[(E)-2-Pyridin-4-ylvinyl]phenyl}cyclopropyl)carbonyl]-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by procedures analogous to those used for thepreparation of example 122. LCMS: m/z 438.2 (M+H)⁺; 460.1 (M+Na)⁺.

Example 212(1R)-1′-[(1-{4-[Cyclopentyl(fluoro)methyl]phenyl}cyclopropyl)carbonyl]-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-oneStep 1. 1-{4-[cyclopentyl(hydroxy)methyl]phenyl}cyclopropanecarbonitrile

To a solution of 1-(4-bromophenyl)cyclopropanecarbonitrile (2.01 g,0.00905 mol) in tetrahydrofuran (30 mL, 0.4 mol) was added 2.5 M ofn-butyllithium in hexane (4.0 mL) at −78° C. and the mixture was stirredat −30° C. for 30 minutes. A solution of cyclopentanecarbaldehyde (0.972g, 0.00990 mol) in THF (2 mL) was added to the above mixture and theresulting mixture was stirred at −78° C. for 2 hours. The reaction wasthen quenched with a small amount of saturated aqueous NH₄Cl solutionfollowed by extraction with ethyl acetate, drying with MgSO₄, andconcentrating under reduced pressure. The crude product was purified byflash chromatography, eluting with 30% AcOEt in hexanes.

Step 2. 1-{4-[cyclopentyl(fluoro)methyl]phenyl}cyclopropanecarbonitrile

1-{4-[Cyclopentyl(hydroxy)methyl]phenyl}cyclopropanecarbonitrile (600.0mg, 0.002486 mol) was dissolved in methylene chloride (10 mL, 0.2 mol),cooled to −78° C., and to the solution was added diethylaminosulfurtrifluoride (0.328 mL, 0.00249 mol) (DAST). The resulting reactionmixture was warmed to rt and stirred at rt for 18 h. The reactionmixture then was poured into ice-water containing NaHCO₃ and theresulting mixture was extracted with CH₂Cl₂ (3×). The combined organicphase was dried over Na₂SO₄, and concentrated to afford the product.

Step 3. 1-{4-[cyclopentyl(fluoro)methyl]phenyl}cyclopropanecarboxylicacid

To a mixture of1-{4-[cyclopentyl(fluoro)methyl]phenyl}cyclopropanecarbonitrile (600.0mg, 0.002466 mol) and 19.4 M of sodium hydroxide in water (0.51 mL) wasadded 1,2-ethanediol (5 mL, 0.09 mol), and the mixture was refluxed at100° C. overnight. After cooling down to rt, the reaction mixture waspoured into water and extracted with ether. The aqueous phase then wasacidified with HCl and extract with ether. Then the organic phase waswashed with brine, dried over MgSO₄, and concentrated to afford thedesired product.

Step 4

The BOP coupling was performed under conditions analogous to thoseoutlined in example 95, step B. LC/MS: 435.2 (M+H⁺).

Example 213(1R)-1′-({1-[4-(Tetrahydro-2H-pyran-4-yloxy)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-oneStep 1. 1-(4-hydroxyphenyl)cyclopropanecarboxylic acid

A solution of 1-(4-methoxyphenyl)cyclopropanecarboxylic acid (0.70 g,0.0036 mol) with 1.0 M of L-Selectride® in tetrahydrofuran (18 mL) wasmicrowave irradiated at 120° C. for 2 hours. The completion of thereaction was achieved after LCMS indicated that the starting materialwas consumed. Then reaction mixture was acidified (pH=2) withconcentrated HCl solution. The mixture was concentrated and the residuewas diluted with water and stirred at rt to precipitate the white solidproduct, which was filtered and dried under vacuum to give the desiredproduct. The structure was confirmed by ¹H NMR.

Step 2.1′-{[1-(4-hydroxyphenyl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

A solution of 1-(4-hydroxyphenyl)cyclopropanecarboxylic acid (0.250 g,0.00140 mol), benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (0.652 g, 0.00147 mol) in N,N-dimethylformamide (2.0mL, 0.026 mol) was stirred at rt for 10 minutes. The solution then wascooled to 0° C. and(1R)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one (0.53 g, 0.0014mol) was added to the solution followed by N,N-diisopropylethylamine(610 μL, 0.0035 mol). The resulting mixture was stirred at roomtemperature overnight. After work-up, 0.95 g of the crude product wasobtained, which was used without further purification.

Step 3

A mixture of(1R)-1′-{[1-(4-hydroxyphenyl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one(10 mg, 0.00003 mol), tetrahydro-4H-pyran-4-ol (6.5 μL, 0.000068 mol),diisopropyl azodicarboxylate (13 μL, 0.000068 mol), andtriphenylphosphine (18 mg, 0.000068 mol) in tetrahydrofuran (200 μL,0.002 mol) was stirred at room temperature overnight. It was purifiedwith prep-HPLC to afford 2.3 mg of product. LCMS: m/z 435.1 (M+H)⁺.

Example 214 tert-Butyl(4-{1-[((1R)-3-oxo-1′H,3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-1′-yl)carbonyl]cyclopropyl}phenoxy)acetate

This compound was prepared by procedures analogous to those in example213, with the exception that step 3 in example 213 was replaced with thefollowing procedure: A mixture of1′-{[1-(4-hydroxyphenyl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one(30 mg, 0.00004 mol), acetic acid, bromo-, 1,1-dimethylethyl ester (9.5μL, 0.000064 mol), and cesium carbonate (42 mg, 0.00013 mol) in dimethylsulfoxide (500 μL, 0.007 mol) was microwave irradiated at 120° C., for10 minutes. The crude product was purified by prep-HPLC. LCMS: m/z 465.1(M+H)⁺; 487.1 (M+Na)⁺.

Example 215(4-{1-[((1R)-3-Oxo-1′H,3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-1′-yl)carbonyl]cyclopropyl}phenoxy)acetonitrile

The title compound was prepared using procedures analogous to those inexample 213, with the exception that step 3 was replaced with thefollowing procedure: a mixture ofl′-{[1-(4-hydroxyphenyl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one(15 mg, 0.000043 mol), bromoacetonitrile (4.3 μL, 0.000064 mol), cesiumcarbonate (28 mg, 0.000086 mol), and tetra-n-butylammonium iodide (1 mg,0.000003 mol) in dimethyl sulfoxide (300 μL, 0.004 mol) was stirred atroom temperature overnight. The crude product was purified withprep-HPLC. LCMS: m/z 390.1 (M+H)⁺; 412.1 (M+Na)⁺.

Example 216(1R)-1′-[(1-{4-[(5-Methylisoxazol-3-yl)methoxy]phenyl}cyclopropyl)carbonyl]-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared using procedures analogous to those describedfor the synthesis of example 215. LCMS: m/z 446.2 (M+H)⁺; 468.2 (M+Na)⁺.

Example 217(1R)-1′-({1-[4-(Cyclopentylmethoxy)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using procedures analogous to thosedescribed in example 213. LC/MS: m/z 433.1 (M+H)⁺; 455.1 (M+Na)⁺.

Example 218(1R)-1′-({1-[4-(Quinolin-3-ylmethoxy)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared using procedures analogous to those describedfor the synthesis of example 213. LC/MS: 492.2 (M+H⁺).

Example 219(1R)-1′-({1-[4-(Quinolin-4-ylmethoxy)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared using procedures analogous to those describedfor the synthesis of example 213. LC/MS: 492.2 (M+H⁺).

Example 220(1R)-1′-({1-[4-(Quinolin-6-ylmethoxy)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared using procedures analogous to those describedfor the synthesis of example 213. LC/MS: 492.2 (M+H⁺).

Example 221(1R)-1′-({1-[4-(Pyridin-3-ylmethoxy)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared using procedures analogous to those describedfor the synthesis of example 215. LC/MS: 442.2 (M+H⁺) and 464.1 (M+Na⁺).

Example 2226-(Trifluoromethyl)-1′-({1-[4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-oneStep 1. tert-butyl3-oxo-6-(trifluoromethyl)-1′H,3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidine]-1′-carboxylate

To a solution of piperidine, 2,2,6,6-tetramethyl-(0.608 mL, 0.00360 mol)in tetrahydrofuran (15.0 mL, 0.185 mol) at −75° C. was addedn-butyllithium in hexane (2.5 M, 2.50 mL). After 15 minutes, asuspension of 6-(trifluoromethyl)nicotinic acid (477.8 mg, 0.002500 mol)in THF (3 mL) was added to the mixture. The mixture was stirred at −55to −40° C. for 2 hours. tert-Butyl 3-oxopyrrolidine-1-carboxylate (370.4mg, 0.002000 mol) in THF (2.0 mL) then was added to the above mixtureand the reaction temperature was maintained at −40° C. The mixture wasstirred at −40° C. for 30 minutes, then slowly warmed up to 0° C. To themixture was added acetic acid (2.00 mL, 0.0352 mol) at 0° C. and thesolution was stirred at room temperature overnight. The reaction mixturewas carefully neutralized with NaHCO₃ and the resulting mixture wasextracted with AcOEt (4×30 mL) The combined organic phase was washedwith brine (30 mL), dried over MgSO₄, and concentrated. The residue waspurified by Combiflash with ethyl acetate/hexane to give the desiredproduct. LC/MS: 359.1 (M+H⁺)

Step 2.6-(trifluoromethyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-onedihydrochloride

tert-Butyl3-oxo-6-(trifluoromethyl)-1′H,3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidine]-1′-carboxylate(0.49 g, 0.0014 mol) was treated with hydrogen chloride in 1,4-dioxane(4.0 M, 2.0 mL) at rt for 1 h. The solvent then was evaporated and theresidue was washed with ether and dried to give the desired product.LC/MS: 332.1 (M+H⁺)

Step 3.6-(Trifluoromethyl)-1′-({1-[4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared using a procedure analogous to the onedescribed in step C of example 94. LC/MS: 471.1 (M+H⁺).

Example 2231′-({1-[4-(Trifluoromethoxy)phenyl]cyclopropyl}carbonyl)-6-(trifluoromethyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared using a procedure analogous to the onedescribed in example 222. LC/MS: 487.1 (M+H⁺).

Example 2241′-{[1-(2,4-Difluorophenyl)cyclopropyl]carbonyl}-6-(trifluoromethyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared using a procedure analogous to the onedescribed in example 222. LC/MS: 439.1 (M+H⁺).

Example 2251′-{[1-(1,3-Benzothiazol-2-yl)cyclopropyl]carbonyl}-6-(trifluoromethyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared using a procedure analogous to the onedescribed in example 222. LC/MS: 460.1 (M+H⁺).

Example 2261′-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-6-(trifluoromethyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared using a procedure analogous to the onedescribed in example 222. LC/MS: 437.1 (M+H⁺).

Example 2274-Fluoro-1′-[(1-quinolin-4-ylcyclopropyl)carbonyl]-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-oneStep 1. tert-butyl4-fluoro-3-oxo-1′H,3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidine]-1′-carboxylate

To a solution of piperidine, 2,2,6,6-tetramethyl-(0.984 mL, 0.00583 mol)in tetrahydrofuran (15.0 mL, 0.185 mol) at −75° C. was added 2.50 M ofn-butyllithium in hexane (4.00 mL). After 15 minutes, a suspension of2-fluoronicotinic acid (0.548 g, 0.00389 mol) in THF (5 mL) was added tothe mixture. Stirring was continued at −55° C. for 1 h. tert-Butyl3-oxopyrrolidine-1-carboxylate (0.60 g, 0.0032 mol) in THF (2.0 mL) wasadded to the above mixture, and the reaction temperature was maintainedat −50 to −40° C. The mixture was stirred at −40° C. for 30 min. andthen slowly allowed to warm to 0° C. To the mixture was added aceticacid (4.0 mL, 0.070 mol) at 0° C. The mixture was stirred at roomtemperature overnight and then was carefully neutralized with NaHCO₃.The resulting mixture was extracted with AcOEt (4×30 mL). The organicphase was washed with brine (30 mL), dried over MgSO₄, and concentrated.The residue was purified by Combiflash with ethyl acetate/hexane to givethe desired product 0.41 g. LC/MS: 309.1 (M+H⁺).

Step 2. 1-quinolin-4-ylcyclopropanecarboxylic acid

A solution of NaOH in water (2 ml, 50%) was added to a mixture ofquinolin-4-ylacetonitrile (0.5 g, 0.002 mol), 1-bromo-2-chloro-ethane(1.0 mL, 0.012 mol), and benzyltriethylammonium chloride (0.1 g, 0.0004mol) at 50° C. After the mixture was stirred at 50° C. for 3 hours,1,2-ethanediol (5 mL, 0.09 mol) was added. Then the reaction mixture wasstirred at 100° C. overnight. The reaction mixture was cooled to roomtemperature and washed with ether (3×). The aqueous layer was acidified(pH=2), and then extracted with ethyl acetate (3×). The combined organiclayer was dried over MgSO₄, filtered, and concentrated to afford thedesired product. LC/MS: 214.1 (M+H⁺).

Step 3

HCl in dioxane (4.0 M, 1 mL) was added to tert-butyl4-fluoro-3-oxo-1′H,3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidine]-1′-carboxylate(25.8 mg, 0.0000837 mol). The reaction mixture was stirred at roomtemperature for 30 minutes before the volatiles was removed to affordthe free amine (hydrochloric acid salt), which was subsequently used inthe coupling reaction. 4-Methylmorpholine (50 μL, 0.0004 mol) was addedto a mixture of 1-quinolin-4-ylcyclopropanecarboxylic acid (17.8 mg,0.0000837 mol),4-fluoro-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-onedihydrochloride (23.5 mg, 0.0000837 mol), and(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate(45.7 mg, 0.0000879 mol) in N,N-dimethylformamide (0.5 mL, 0.006 mol).The reaction mixture was stirred at room temperature for 2 hours. Thecrude product was purified by prep-LCMS. LC/MS: 402.1 (M+H⁺).

Example 2281′-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-4-fluoro-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared using procedures analogous to those inexample 227. LC/MS: 387.1 (M+H⁺).

Example 2297-Fluoro-1′-[(1-{4-[(trifluoromethyl)thio]phenyl}cyclopropyl)carbonyl]-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-oneStep 1. 1-{4-[(trifluoromethyl)thio]phenyl}cyclopropanecarboxylic acid

A mixture of {4-[(trifluoromethyl)thio]phenyl}acetonitrile (1.15 g,0.00529 mol), 1-bromo-2-chloro-ethane, (880 μL, 0.010 mol),benzyltriethyl ammonium chloride (70 mg, 0.0003 mol) and 1.5 ml of 50%NaOH-water (w/w) solution was kept at 50° C. with stirring for 3 hours.LCMS data supported that the reaction was complete. To the abovesolution 1,2-ethanediol (10 mL, 0.2 mol) was added. The mixture washeated at 100° C. overnight. After work-up 1.2 g of solid product wasobtained. LC/MS: 387.1 (M+H⁺).

Step 2. tert-butyl4-fluoro-3-oxo-1′H,3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidine]-1′-carboxylate

To a solution of 2,2,6,6-tetramethyl-piperidine, (0.984 mL, 0.00583 mol)in tetrahydrofuran (15.0 mL, 0.185 mol) at −75° C. was addedn-butyllithium in hexane (2.50 M, 4.00 mL). After 15 min, a suspensionof 2-fluoronicotinic acid (0.548 g, 0.00389 mol) in THF (5 mL) was addedto the mixture. The mixture was kept at −55° C. with stirring for 1hour. tert-Butyl 3-oxopyrrolidine-1-carboxylate (0.60 g, 0.0032 mol) inTHF (2.0 mL) was added to the above mixture while the reactiontemperature was maintained at −50 to −40° C. The mixture was stirred at−40° C. for 30 minutes and then slowly allowed to warm to 0° C. To themixture was added acetic acid (4.0 mL, 0.070 mol) at 0° C. and thereaction was allowed to gradually warm to room temperature with stirringovernight. The reaction mixture was carefully neutralized with NaHCO₃and the resulting mixture was extracted with AcOEt (4×30 mL). Thecombined organic phase was washed with brine (30 mL), dried over withMgSO₄, and concentrated. The residue was purified by Combiflash withethyl acetate/hexane to give the desired product (0.41 g). LC/MS: 309.1(M+H⁺).

Step 3.7-Fluoro-1′-[(1-(4-[(trifluoromethyl)thio]phenyl}cyclopropyl)carbonyl]-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

The title compound was prepared using a procedure analogous to thatdescribed in step 3 of example 227. LC/MS: 453.1 (M+H⁺).

Example 2301′-{[1-(4-Bromophenyl)cyclopropyl]carbonyl}-7-fluoro-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was formed using procedures analogous to those in example229. LC/MS: 432.1 (M+H⁺).

Example 231(1R)-1′-{[1-(1,3-Benzothiazol-2-yl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to that instep B of example 95. The prerequisite1-(1,3-benzothiazol-2-yl)cyclopropanecarboxylic acid was prepared byusing a procedure analogous to that used in step 2 of example 227.LC/MS: 392.1 (M+H⁺).

Example 2321′-{[1-(1,3-Benzothiazol-2-yl)cyclopropyl]carbonyl}-6-chloro-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-oneStep 1. tert-butyl6-chloro-3-oxo-1′H,3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidine]-1′-carboxylate

To a solution of 2,2,6,6-tetramethyl-piperidine, (508 mg, 0.00360 mol)in tetrahydrofuran (15.0 mL, 0.185 mol) at −75° C. was added 2.50 M ofn-butyllithium in hexane (2.50 mL). After 15 minutes, a suspension of6-chloronicotinic acid (393.9 mg, 0.002500 mol) in THF (2 mL) was added.The mixture was stirred at −55° C. to −20° C. for 2 hours, then wasre-cooled to −20° C. tert-Butyl 3-oxopyrrolidine-1-carboxylate (370.4mg, 0.002000 mol) in THF (2.0 mL) was added to the above mixture and thereaction temperature was maintained at −40° C. After stirring for 30minutes, the reaction was allowed to slowly warm up to 0° C. To themixture was added acetic acid (2.00 mL, 0.0352 mol) at 0° C. and themixture was stirred at room temperature overnight. The reaction mixturewas carefully neutralized with NaHCO₃. The resulting mixture wasextracted with AcOEt (4×30 mL). The combined organic layer was washedwith brine (30 mL), dried over MgSO₄, and concentrated. The residue waspurified by Combiflash with ethyl acetate/hexane to give the desiredproduct.

Step 2.1′-{[1-(1,3-Benzothiazol-2-yl)cyclopropyl]carbonyl}-6-chloro-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

The title compound was prepared by a procedure analogous to that in step3 of example 227. LC/MS: 426.6 (M+H⁺).

Example 2336-Chloro-1′-({1-[4-(trifluoromethoxy)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using an analogous procedure to thatdescribed above for the synthesis of example 232. LC/MS: 453.6 (M+H⁺).

Example 2346-Chloro-1′-{[1-(2-fluorophenyl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using an analogous procedure to thatdescribed above for the synthesis of example 232. LC/MS: 387.6 (M+H⁺).

Example 235(1R)-1′-({1-[4-(4-Chlorophenyl)-1,3-thiazol-2-yl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using an analogous procedure to thatdescribed above for the synthesis of example 231. LC/MS: 452.8 (M+H⁺).

Example 2364-(1-{[(1R)-3-Oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)benzonitrile

A degassed mixture of(1R)-1′-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one(36.0 mg, 0.0000979 mol) (example 83), zinc cyanide (23.4 mg, 0.000196mol), bis(tri-t-butylphosphine)palladium (31 mg, 0.000059 mol) and zinc(11.5 mg, 0.000176 mol) powder in N-methylpyrrolidinone (1.00 mL, 0.0104mol) was heated at 150° C. for 16 hours. The reaction mixture was cooledto room temperature, diluted with EtOAc, filtered through a pad ofcelite and the solid was washed with EtOAc. The filtrate was washed with2 N NH₄OH (20 mL) and brine successively, dried over magnesium sulfate,filtered and concentrated in vacuo. The residue was purified byCombiflash with 10-20% EtOAc/hexanes to give the product. LC/MS: 359.1(M+H⁺).

Example 238(1R)-1′-{[1-(4-Bromophenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-oneStep 1. 1-(4-bromophenyl)cyclopropanecarboxylic acid

Sodium hydroxide, 50% aqueous solution (60.4 mL, 1.58 mol) was added toa mixture of 4-bromobenzeneacetonitrile (30 g, 0.2 mol),benzyltriethylammonium chloride (2.8 g, 0.012 mol), and1-bromo-2-chloroethane (26.5 mL, 0.320 mol) at 50° C. for 5 hours.1,2-ethanediol (306.0 mL, 5.491 mol) was added to the mixture and theresulting mixture was heated at 100° C. overnight. The mixture waspoured into ice-water (60 mL) and was extracted with ethyl ether (2×150mL). The aqueous phase was acidified (pH=2) with 1N HCl and wasextracted with ethyl acetate (3×50 mL). The combined organic phase waswashed with brine (100 mL), dried over MgSO₄, filtered, and concentratedunder reduced pressure. The residue was the desired product (36.6 g)which was directly used in next step without further purification. ¹HNMR confirmed the structure of the product.

Step 2

To a stirred solution of 1-(4-bromophenyl)cyclopropanecarboxylic acid(1.616 g, 0.006704 mol) in anhydrous N,N-dimethylformamide (12.0 mL,0.155 mol) at room temperature was added(7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonicacid-(1R)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (1:1) (2.569 g,0.006095 mol, example 96, steps 1-2),benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(3.057 g, 0.006704 mol), followed by N,N-diisopropylethylamine (4.27 mL,0.0244 mol). The resulting clear solution was stirred at temperature for17 hours. LCMS showed that the reaction was complete. The reaction wasquenched with saturated aqueous NaHCO₃ (50 mL), and the reaction mixturewas extracted with EtOAc (2×).

The combined organic layer was washed with brine, dried over magnesiumsulfate, filtered and concentrated in vacuo. The residue was purified byCombiflash with 30-70% EtOAc/hexanes to give the product as a colorlesssolid (2.258 g, 90% in yield). LC/MS (M+H⁺)=412.1.

Example 239(1R)-1′-({1-[4-(Pyrrolidin-1-ylcarbonyl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

A mixture of(1R)-1′-{[1-(4-bromophenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one(68.0 mg, 0.000165 mol, example 238), pyrrolidine (42 μL, 0.00049 mol),molybdenum hexacarbonyl (44 mg, 0.00016 mol),trans-di(μ-acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium (II)(16 mg, 0.000016 mol) and 1,8-diazabicyclo[5.4.0] undec-7-ene (76 μL,0.00049 mol) (DBU) in anhydrous tetrahydrofuran (2.0 mL, 0.025 mol) in amicrowave vial was irradiated with microwaves to 150° C. for 30 minutes.The reaction mixture was filtered. The filtrate was purified byprep-HPLC to afford the product as a solid (55.9 mg, 79% in yield).LC/MS (M+H⁺)=431.1.

Example 2404-(1-{[(1R)-3-Oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)benzohydrazide

A mixture of(1R)-1′-{[1-(4-bromophenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one(229 mg, 0.000555 mol, example 238), hydrazine (53 μL, 0.0017 mol),molybdenum hexacarbonyl (0.150 g, 0.000555 mol),trans-di(u-acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium (II)(54 mg, 0.000056 mol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (254 μL,0.00167 mol) (DBU) in anhydrous N-methylpyrrolidinone (2.0 mL, 0.021mol) and tetrahydrofuran (1.0 mL, 0.012 mol) in a microwave vial wasirradiated with microwaves to 170° C. for 30 minutes. The reactionmixture was diluted with MeOH and filtered. The filtrate was purified byprep-HPLC to afford the product as a solid (3.2 mg, 2% in yield for twosteps). LC/MS (M+H⁺)=392.1.

Example 241N-Methyl-4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)benzamide

This compound was prepared by a procedure analogous to that outlinedabove for the synthesis of example 238. LC/MS (M+H⁺)=391.2.

Example 2424-(1-{[(1R)-3-Oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)benzenecarbothioamide

A mixture of4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)benzonitrile(126 mg, 0.000352 mol, example 236), 7.34 M of ammonium sulfide in water(145 μL) (50 wt % in water) in methanol (3.5 mL, 0.087 mol) in amicrowave vial was irradiated with microwaves at 100° C. for 60 minutes.The reaction was quenched with water (15 mL) and the reaction mixturewas extracted with EtOAc (2×). The combined organic layer was washedwith brine, dried over magnesium sulfate, filtered and concentrated invacuo. The residue was purified by Combiflash with 40-90% EtOAc/hexanesto afford the product as a yellow solid (65.5 mg, 48% in yield).(M+H⁺)=393.1.

Example 243(1R)-1′-[(1-{4-[2-(Trifluoromethyl)-1H-imidazol-4-yl]phenyl}cyclopropyl)carbonyl]-31′-spiro[2-benzofuran-1,3′-pyrrolidin]-3-oneStep 1. methyl 1-phenylcyclopropanecarboxylate

Methyl iodide (2.8 mL, 0.045 mol) was added to a mixture of1-phenylcyclopropane carboxylic acid (4.9 g, 0.030 mol) and potassiumcarbonate (8.3 g, 0.060 mol) in N,N-dimethylformamide (40 mL, 0.5 mol)at room temperature and then stirred for 1 hour. The mixture was dilutedwith ether, washed with water (×2) and brine successively, dried andconcentrated to give the desired product.

Step 2. methyl 1-[4-(chloroacetyl)phenyl]cyclopropanecarboxylate

Aluminum trichloride (7.9 g, 0.060 mol) was added in portions to amixture of methyl 1-phenylcyclopropanecarboxylate (3.5 g, 0.020 mol) andchloroacetyl chloride (2.0 mL, 0.026 mol) in carbon disulfide (40 mL,0.7 mol) at 15-25° C. and then the reaction mixture was stirred at roomtemperature for 2 hours. The mixture was poured into conc. HCl (10 mL)in ice (100 g) and then extracted with ether. The ether extract waswashed with brine, dried and concentrated. The product was purified byCombiFlash using hexane/EtOAc (max.EA 20%). The final product wasanalyzed by ¹H NMR, which showed that the product was a mixture of paraand meta substituted isomers with a ratio of 3:2.

Step 3.1-{4-[2-(trifluoromethyl)-1H-imidazol-4-yl]phenyl}cyclopropanecarboxylicacid

A mixture of methyl 1-[4-(chloroacetyl)phenyl]cyclopropanecarboxylate(0.20 g, 0.00079 mol) and 2,2,2-trifluoroethanimidamide (0.18 g, 0.0016mol) in ethanol (5.0 mL, 0.086 mol) was refluxed for 4 hours. Themixture was diluted with ethyl acetate, washed with sat'd. NaHCO₃ andbrine successively, dried and concentrated. The residue was trituratedwith ether and the filtered to provide the methyl ester. LC-MS: 311.1(M+H)⁺ The ester was hydrolyzed using lithium hydroxide (6.0 eq.) inmethanol/water (3:1) under reflux for 30 minutes. The reaction mixturewas then concentrated and the pH was adjusted to 2˜3 by adding 1N HCl.The resulting precipitate was filtered and dried to afford the desiredproduct. LC-MS: 297.1 (M+H)'

Step 4.(1R)-1′-[(1-{4-[2-(Trifluoromethyl)-1H-imidazol-4-yl]phenyl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

The title compound was prepared using an analogous procedure to thatoutlined in step 2 of example 238. LC/MS: 468.2 (M+H⁺).

Example 244(1R)-1′-({1-[4-(1-Methyl-1H-pyrazol-3-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

To a solution of(1R)-1′-{[1-(4-bromophenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one(20 mg, 0.00005 mol, example 238) in tetrahydrofuran (0.2 mL, 0.002 mol)were added tris(dibenzylideneacetone)dipalladium(0) (0.2 mg, 0.0000002mol), tri-tert-butylphosphine (0.12 mg, 5.8×10⁻⁷ mol),(1-methyl-1H-pyrazol-3-yl)boronic acid (6.8 mg, 0.0000534 mol). Themixture was heated at 120° C. under microwave for 30 minutes. Thereaction mixture then was filtered and the filtrate was diluted withmethanol and purified with prep-HPLC to afford the desired product.LC/MS: 414.2 (M+H⁺).

Example 245N-Cyclopropyl-4′-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)biphenyl-4-carboxamide

This compound was prepared by using an analogous method to that used forthe synthesis of example 244. LC/MS: 493.2 (M+H⁺).

Example 246(1R)-1′-[(1-{4-[5-(Trifluoromethyl)-1H-1,2,4-triazol-3-yl]phenyl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

A mixture of4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)benzenecarbothioamide(39 mg, 0.000099 mol, example 242) and trifluoroacetic acid hydrazide(28 mg, 0.00020 mol) in anhydrous N,N-dimethylformamide (1.0 mL, 0.013mol) in a microwave vial was irradiated with microwaves at 120° C. for30 minutes. LCMS showed there was no product formation and some startingmaterial was converted to nitrile. 7.34 M of ammonium sulfide in water(27 μL) and triethylamine (28 μL, 0.00020 mol) then was added. Thereaction mixture was irradiated with microwaves at 100° C. for 1.5hours. The crude reaction mixture was purified by prep-HPLC to give theproduct as a colorless solid (6.6 mg, 14% in yield) as well as recoveredstarting material (16.7 mg, 43% recovery of S.M.). LC/MS (M+H⁺)=469.2

Example 247(1R)-1′-({1-[4-(1H-tetrazol-5-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

A mixture of4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-yl]carbonyl}cyclopropyl)benzonitrile(50.0 mg, 0.000140 mol, example 236), sodium azide (109 mg, 0.00167 mol)and ammonium chloride (89.6 mg, 0.00167 mol) in anhydrousN,N-dimethylformamide (1.4 mL, 0.018 mol) in a microwave vial wasirradiated with microwaves to 180° C. for 40 minutes. LCMS showed thereaction was complete. The reaction mixture was filtered and thefiltrate was purified by prep-HPLC to give the product as a colorlesssolid (44.5 mg, 80% in yield). LC/MS (M+H⁺)=402.1.

Example 248(1R)-1′-({1-[4-(2-Amino-1,3-oxazol-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-oneStep 1. 1-[4-(2-amino-1,3-oxazol-4-yl)phenyl]cyclopropanecarboxylic acid

A mixture of methyl 1-[4-(chloroacetyl)phenyl]cyclopropanecarboxylate(0.20 g, 0.00079 mol, example 243, steps 1 & 2) and urea (0.095 g,0.0016 mol) in ethanol (5.0 mL, 0.086 mol) was refluxed overnight. Themixture was diluted with ethyl acetate and washed with sat'd. NaHCO₃,brine, dried and concentrated. The methyl ester was purified byCombiFlash using CH₂Cl₂/EtOAc (max. EtOAc 100%). The ester washydrolyzed using lithium hydroxide (6.0 eq.) in methanol/THF and thenacidified by adding 1 N HCl. The solvent was removed under vacuum andthe crude product was used in the next step. LC-MS: 259.2 (M+H⁺) methyleater; 245.2 (M+H⁺) acid

Step 2

The BOP mediated coupling was performed using a procedure analogous tothat described in step 2 of example 338.

Example 249(1R)-1′-{[1-(4-Pyrimidin-5-ylphenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

A mixture of(1R)-1′-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one(15.0 mg, 0.0000408 mol, prepared by a procedure analogous to that instep 1 of example 173), pyrimidin-5-ylboronic acid (5.6 mg, 0.000045mol), tris(dibenzylidene acetone)dipalladium(0) (2 mg, 0.000002 mol),and tri-tert-butylphosphine (0.8 mg, 0.000004 mol), cesium carbonate (16mg, 0.000049 mol) in 1,4-dioxane (1.0 mL, 0.013 mol) was microwaveirradiated at 90° C. for 30 minutes. The crude product was purified withprep-HPLC. LC/MS: 412.2 (M+H⁺).

Example 250 (1R)-1%({1-[4-(6-Fluoropyridin-3-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-oneStep 1.(1R)-1′-({1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

To a solution of(1R)-1′-{[1-(4-bromophenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one(0.55 g, 0.0013 mol, example 238) and4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (0.37 g,0.0015 mol) in 1,4-dioxane (8.0 mL, 0.10 mol) were added potassiumacetate (0.39 g, 0.0040 mol), 1,1′-bis(diphenylphosphino) ferrocene (40mg, 0.00007 mol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane (1:1) (50 mg,0.00007 mol) under nitrogen and the reaction was stirred at 80° C.overnight. The mixture was filtered through celite and concentrated. Theproduct was purified by CombiFlash using CH₂Cl₂/EtOAc (max EA 60%).LC-MS: 460.2 (M+H⁺)

Step 2

To a solution of(1R)-1′-({1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one(130 mg, 0.00029 mol) in 1,4-dioxane (1 mL, 0.01 mol) were added5-bromo-2-fluoropyridine (0.060 mL, 0.00058 mol),tris(dibenzylideneacetone)dipalladium(0) (1 mg, 0.000001 mol),tri-tert-butylphosphine (0.71 mg, 0.0000035 mol) and potassium fluoride(56 mg, 0.00096 mol). The mixture was heated at 110° C. under nitrogenfor 30 minutes. The mixture was diluted with ethyl acetate, washed withwater and brine successively, dried and concentrated. The product waspurified by CombiFlash using CH₂Cl₂/EtOAc (max.EA 30%). LC-MS: 429.2(M+H⁺)

Example 251(1R)-1′-({1-[4-(6-Pyrrolidin-1-ylpyridin-3-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

A mixture of(1R)-1′-({1-[4-(6-fluoropyridin-3-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one(20.0 mg, 0.0000467 mol, example 250), pyrrolidine (7.8 μL, 0.000093mol) in dimethyl sulfoxide (0.5 mL, 0.007 mol) was heated at 100° C. ina sealed tube for 5 hours. The product was purified by prep-HPLC. LC-MS:480.2 (M+H⁺)

Example 252N-Cyclopropyl-5-[4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]pyridine-2-carboxamideStep 1. 5-bromopyridine-2-carboxylic acid

Lithium hydroxide, monohydrate (0.39 g, 0.0092 mol) was added to amixture of 5-bromopyridine-2-carboxylic acid methyl ester (0.25 g,0.0012 mol) in tetrahydrofuran (4.8 mL, 0.059 mol) and water (2.0 mL)and the reaction mixture was refluxed for 30 minutes. The reactionmixture was concentrated and was adjusted to be acidic (pH=˜4) by adding1 N HCl. The product was extracted with ethyl acetate and the combinedextract was concentrated to give the desired product. LC-MS: 202.0/204.0(M+H⁺)

Step 2. 5-bromo-N-cyclopropylpyridine-2-carboxamide

N,N-Diisopropylethylamine (0.69 mL, 0.0040 mol) was added to a mixtureof 5-bromopyridine-2-carboxylic acid (400 mg, 0.002 mol),cyclopropylamine (0.16 mL, 0.0024 mol) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(1.1 g, 0.0024 mol) in N,N-dimethylformamide (9.4 mL, 0.12 mol) at 0° C.and the mixture was stirred overnight at room temperature. The mixturewas diluted with ethyl acetate, washed with water and brinesuccessively, dried over sodium sulfate, filtered and concentrated. Theproduct was purified by CombiFlash eluting with CH₂Cl₂/EtOAc (max.EtOAc20%). LC-MS: 241.1/243.1 (M+H⁺)

Step 3

The title compound was prepared by using a procedure analogous to thatdescribed in example 250. LC-MS: 494.2 (M+H⁺)

Example 253N-Methyl-5-[4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]pyridine-2-carboxamide

This compound was prepared using an analogous procedure to that outlinedabove in example 250. LC/MS: 468.2 (M+H⁺).

Example 254(1R)-1′-({1-[4-(Methylsulfonyl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-oneStep 1.(1R)-1′-({1-[4-(methylthio)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared using a procedure analogous to that used instep 2 of example 238. LC/MS: 380.1 (M+H⁺).

Step 2

To a solution of(1R)-1′-({1-[4-(methylthio)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one(50 mg, 0.00008 mol) and methylene chloride (300 μL, 0.005 mol) wasadded m-chloroperbenzoic acid (97 mg, 0.00040 mol) in portions. Thesolution was stirred at room temperature overnight. The product waspurified by prep-HPLC to afford the desired product (17.8 mg). LCMS: m/z412.0 (M+H⁺); 434.0 (M+Na⁺).

Example 255(1R)-1′-[(1-{4-[(Trifluoromethyl)thio]phenyl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared using procedures analogous to those used insteps 1-2 of example 238. LCMS: m/z 434.0 (M+H⁺). 456.0 (M+Na⁺).

Example 256(1R)-1′-{[1-(4-Chloro-2-fluorophenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared using procedures analogous to those used insteps 1-2 of example 238. LCMS: m/z 386.4 (M+H⁺).

Example 257(1R)-1′-({1-[4-(2-Oxopyridin-1(2H)-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

To a solution of(1R)-1′-{[1-(4-bromophenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one(30.0 mg, 0.0000728 mol, example 238), pyrid-2-one (8.30 mg, 0.0000873mol) in 1,4-dioxane (2 mL, 0.02 mol) were added(1S,2S)—N,N′-dimethylcyclohexane-1,2-diamine (2.1 mg, 0.000014 mol),copper(I) iodide (1.4 mg, 0.0000073 mol), and potassium carbonate (21.1mg, 0.000153 mol). The mixture was heated at 160° C. for 60 minutes. Thereaction mixture was filtered, and the filtrate was concentrated andpurified using prep-HPLC. LC/MS: 427.1 (M+H⁺).

Example 258 Methyl4-[4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]piperazine-1-carboxylateStep 1. tert-butyl 1-(4-bromophenyl)cyclopropanecarboxylate

Isobutylene (80.0 mL, 0.847 mol) was passed through a mixture of1-(4-bromophenyl)cyclopropanecarboxylic acid (10.0 g, 0.0415 mol,example 238, step 1) and sulfuric acid (1.0 mL, 0.019 mol) at −78° C.The mixture was sealed and was stirred at room temperature overnight.The isobutylene was evaporated at room temperature and the residue wasdissolved in ethyl acetate (100 mL), and washed with water and brinesuccessively. The organic layer was dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to give the desired product.

Step 2. tert-butyl4-{4-[1-(tert-butoxycarbonyl)cyclopropyl]phenyl}piperazine-1-carboxylate

A mixture of tert-butyl 1-(4-bromophenyl)cyclopropanecarboxylate (297.2mg, 0.001000 mol), tert-butyl piperazine-1-carboxylate (186.2 mg,0.001000 mol), sodium tert-pentoxide (110.1 mg, 0.001000 mol),[1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II), complexwith dichloromethane (1:1) (24.5 mg, 0.0000300 mol) and1,1′bis(diphenylphosphino)ferrocene (16.6 mg, 0.0000300 mol) wasdeaerated and then charged with nitrogen. To the mixture was addedtoluene (3.0 mL, 0.028 mol), and the resulting mixture was heated at100° C. overnight. The mixture was poured into ice-water and wasextracted with ethyl acetate (4×10 mL). The combined organic layer waswashed with water and brine successively, dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The residue was purified byCombiflash with ethyl acetate/hexane.

Step 3. methyl4-{4-[1-(tert-butoxycarbonyl)cyclopropyl]phenyl}piperazine-1-carboxylate

tert-Butyl4-{4-[1-(tert-butoxycarbonyl)cyclopropyl]phenyl}piperazine-1-carboxylate(16.0 mg, 0.0000397 mol) was treated with hydrogen chloride in1,4-dioxane (4.0 M, 0.20 mL) at rt for 30 min. The solvent wasevaporated under reduced pressure, and the residue was dissolved inacetonitrile (1.0 mL, 0.019 mol) and was treated withN,N-diisopropylethylamine (20.0 μL, 0.000115 mol) and methylchloroformate (5.0 μL, 0.000065 mol). After 30 min, the solvent wasevaporated under reduced pressure and the residue was the desiredproduct, which was directly used in the next step without furtherpurification. LC/MS: 361.2 (M+H⁺).

Step 4

The title compound was prepared using a procedure analogous to that usedin step 2 of example 238. LC/MS: 476.4 (M+H⁺).

Example 259(1R)-1′-[(1-{4-[4-(Methylsulfonyl)-2-oxopiperazin-1-yl]phenyl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-oneStep 1. tert-butyl3-oxo-4-[4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]piperazine-1-carboxylate

This compound was prepared using a procedure analogous to that usedabove for the synthesis of example 257. LC/MS: 532.2 (M+H⁺).

Step 2.(1R)-1′-({1-[4-(2-oxopiperazin-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

To a solution of tert-butyl3-oxo-4-[4-(1-{[(1R)-3-oxo-1H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]piperazine-1-carboxylate(180 mg, 0.00034 mol) in methanol (2 mL, 0.05 mol) was added 4 M ofhydrogen chloride in 1,4-dioxane (0.4 mL) and the mixture was stirred atrt for 3 hours and then concentrated. LC/MS: 432.2 (M+H⁺).

Step 3

To a solution of(1R)-1′-({1-[4-(2-oxopiperazin-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one(36 mg, 0.000083 mol) in acetonitrile (0.5 mL, 0.01 mol) were addedtriethylamine (29 μL, 0.00021 mol) and methanesulfonyl chloride. Afterstirring at rt for 3 hours, the crude product was isolated and purifiedby prep-HPLC. LC/MS: 510.2 (M+H⁺).

Example 2607-Fluoro-1′-[(1-{-4-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-oneStep 1. 1-(4-bromophenyl)cyclopropanecarbonitrile

Sodium hydroxide (50% aqueous solution, 29.3 g, 0.505 mol) was added toa mixture of 4-bromo-benzeneacetonitrile (9.80 g, 0.0500 mol),benzyltriethylammonium chloride (0.90 g, 0.0040 mol), ethane, and1-bromo-2-chloro-(14.5 g, 0.101 mol) at 50° C. overnight. The mixturewas poured into ice-water (80 mL) and was extracted with ethyl ether(4×50 mL). The combined organic phase was washed with HCl aqueoussolution (1N, 20 mL) and brine (2×30 mL) successively, dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas the desired product, which was directly used in the next stepwithout further purification.

Step 2.1-{4-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}cyclopropanecarbonitrile

To a solution of 1-(4-bromophenyl)cyclopropanecarbonitrile (600 mg,0.003 mol), 3-(trifluoromethyl)-1H-pyrazole (441 mg, 0.00324 mol) intoluene (2 mL, 0.02 mol) and N,N-dimethylformamide (3 mL, 0.04 mol) wereadded (1S,2S)—N,N′-dimethylcyclohexane-1,2-diamine (77 mg, 0.00054 mol),copper(I) iodide (51 mg, 0.00027 mol), and potassium carbonate (784 mg,0.00567 mol). The mixture was microwave irradiated at 200° C. for 60minutes and then filtered. The filtrate was diluted with methanol, andthe product from the filtrate was isolated and purified using prep-HPLC.Additional product could be obtained from the precipitate by dissolvingthe precipitate in EtOAc, washing with satd. NaHCO₃, brine, drying withMgSO₄, and concentrating for purification.

Step 3.1-{4-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}cyclopropanecarboxylicacid

To a solution of sodium hydroxide in water (19.4 M, 0.1 mL) was added1,2-ethanediol (2 mL, 0.03 mol) and the mixture was refluxed at 120° C.for 20 hours. After cooling to room temperature, the reaction mixturewas poured into water and washed with ether. The aqueous solution wasacidified with HCl and extracted with ether. The organic phase of theextraction was washed with brine, dried over MgSO₄, and concentrated toafford the product.

Step 4

The title compound was prepared using a procedure analogous to thatdescribed for the synthesis of example 94.

Example 261N-[4-(1-{[(1R)-3-Oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]cyclopropanecarboxamideStep 1. tert-butyl1-{4-[(tert-butoxycarbonyl)amino]phenyl}cyclopropanecarboxylate

A mixture of tert-butyl 1-(4-bromophenyl)cyclopropanecarboxylate (320.0mg, 0.001077 mol, example 258, step 1), t-butyl carbamate (180.0 mg,0.001536 mol), sodium benzylate (175.01 mg, 0.0015075 mol),tris(dibenzylideneacetone)dipalladium(0) (16.5 mg, 0.0000180 mol) andtri-tert-butylphosphine (18.8 mg, 0.0000929 mol) in toluene (3.0 mL,0.028 mol) was deaerated and then charged with nitrogen. The resultingmixture was heated at 100° C. overnight. After cooling, the mixture wasfiltered through a pad of celite and washed with ethyl acetate. Thefiltrate was concentrated and the residue was purified by Combiflashwith ethyl acetate/hexane to give the desired product.

Step 2. 1-(4-aminophenyl)cyclopropanecarboxylic acid

4.0 M HCl in dioxane was added to tert-butyl1-{4-[(tert-butoxycarbonyl)amino]phenyl}cyclopropanecarboxylate (160 mg,0.00048 mol). After stirring at rt for 2 h, the volatiles were removedin-vacuo and the resulting residue was used in the next step withoutfurther purification.

Step 3.(1S)-1′-{[1-(4-aminophenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

4-Methylmorpholine (260 μL, 0.0024 mol) was added to a mixture of1-(4-aminophenyl)cyclopropanecarboxylic acid (0.48 mmol, 0.00048 mol),[(1R,4S)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonicacid-(1S)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (1:1) (2.0×10⁻²mg, 0.00048 mol), (benzotriazol-1-yloxy)tripyrrolidino phosphoniumhexafluorophosphate (261 mg, 0.000502 mol), orbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(222 mg, 0.000502 mol) in N,N-dimethylformamide (1.5 mL, 0.019 mol). Thereaction mixture was stirred at rt for 2 h. The crude product waspurified by prep-LCMS. LC/MS: 349.0 (M+H⁺).

Step 4.N-[4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]cyclopropanecarboxamide

Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(17 mg, 0.000038 mol) was added into a solution of(1R)-1′-{[1-(4-aminophenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one(12 mg, 0.000034 mol), cyclopropanecarboxylic acid (3.0 mL, 0.000038mol) and 4-methylmorpholine (15 μL, 0.00014 mol) inN,N-dimethylformamide (0.5 mL, 0.006 mol). The reaction mixture wasstirred at rt for 2 h. It was purified by prep-LCMS. LC/MS: 417.2(M+H⁺).

Example 262N-[4-(1-{[(1R)-3-Oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]benzenesulfonamide

This compound was prepared by using procedures analogous to those weredescribed in step 1 of example 202, and in steps 2-3 of example 261.LC/MS: 489.2 (M+H⁺).

Example 263 Methylallyl[4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]carbamateStep 1. tert-butyl 1-[4-(allylamino)phenyl]cyclopropanecarboxylate

This compound was prepared from the N-2-propenyl-2-propen-1-amine usingthe coupling protocol outlined in example 258, step 2. The other majorproduct was tert-butyl1-[4-(diallylamino)phenyl]cyclopropanecarboxylate.

Step 2. 1-{4-[allyl(methoxycarbonyl)amino]phenyl}cyclopropanecarboxylicacid

Methyl chloroformate (34 μL, 0.00044 mol) was added to a mixture oftert-butyl 1-[4-(allylamino)phenyl]cyclopropanecarboxylate (6.0×10⁻¹ mg,0.00022 mol) and triethylamine (92 μL, 0.00066 mol) in acetonitrile (1.0mL, 0.019 mol) at rt. The reaction mixture was stirred at rt for 30minutes, then was washed with water, and then extracted with EtOAc (3×).The organic layers were combined and concentrated. To the residue wasadded 4.0M HCl in dioxane and the reaction was stirred at rt for 2 h.The solvent was removed in-vacuo and used in the following step. LC/MS:276.2 (M+H⁺).

Step 3

The title compound was prepared by using a procedure analogous to thatin step 3 of example 261. LC/MS: 447.2 (M+H⁺).

Example 264(1R)-1′-({1-[4-(1H-1,2,4-Triazol-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure similar to that outlinedfor the synthesis of example 257. LC/MS: 401.1 (M+H⁺).

Example 265(1R)-1′-[(1-Quinolin-6-ylcyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure similar to that outlinedfor the synthesis of example 238. LC/MS: 385.2 (M+H⁺).

Example 266(1R)-1′-[(1-Pyridin-4-ylcyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a method similar to that outlined inthe synthesis of example 238, beginning with ethyl1-pyridin-4-ylcyclopropanecarboxylate. LC/MS: 335.1 (M+H⁺).

Example 267(1R)-1′-[(1-Quinolin-4-ylcyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a method similar to that outlined inthe synthesis of example 238. LC/MS: 385.1 (M+H⁺).

Example 268(1R)-1′-[(1-Quinolin-2-ylcyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a method similar to that outlined inthe synthesis of example 238. LC/MS: 385.2 (M+H⁺).

Example 269(1R)-1′[(1-Pyridin-2-ylcyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a method similar to that outlined inthe synthesis of example 238, beginning with methyl1-pyridin-2-ylcyclopropanecarboxylate. LC/MS: 335.1 (M+H⁺).

Example 270(1R)-1′-{[1-(1,3-Benzothiazol-2-yl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a method similar to that outlined inthe synthesis of example 238. LC/MS: 391.1 (M+H⁺).

Example 2712-(1-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}pyrrolidine-3-yl)-1,3-thiazoleStep 1. tert-butyl3-hydroxy-3-(1,3-thiazol-2-yl)pyrrolidine-1-carboxylate

1.600 M of n-Butyllithium in hexane (1.0×10⁻¹ mL) was added to1,3-thiazole (0.958 mL, 0.0135 mol) in THF (20 mL) at −78° C. After 30minutes, tert-butyl 3-oxopyrrolidine-1-carboxylate (2.50 g, 0.0135 mol)in THF (10 mL) was added, and the mixture was slowly warmed to roomtemperature overnight. The reaction was quenched with water, and thereaction mixture was extracted with ethyl acetate, dried with MgSO₄,filtered and concentrated. The residue was purified by flash column (50%EtOAc/hexanes to pure EtOAc) to give the desired product (2.57 g, 70%).

Step 2. 2-(2,5-dihydro-1H-pyrrol-3-yl)-1,3-thiazole trifluoroacetate

tert-Butyl 3-hydroxy-3-(1,3-thiazol-2-yl)pyrrolidine-1-carboxylate (1.0g, 0.0037 mol) was dissolved in trifluoroacetic acid (10.0 mL, 0.130mol) under N₂ at rt. The reaction flask was wrapped with aluminum foiland the mixture was stirred under reflux for 3 h. After cooling to rtthe reaction mixture was concentrated in vacuo and used directly for thenext step without further purification.

Step 3. 2-pyrrolidin-3-yl-1,3-thiazole trifluoroacetate

To a solution of 2-(2,5-dihydro-1H-pyrrol-3-yl)-1,3-thiazoletrifluoroacetate (2.49 g, 0.00936 mol) in methanol (100.0 mL, 2.469 mol)was added platinum dioxide (320 mg, 0.0014 mol) and the resultingmixture was hydrogenated on par shaker at 56 psi for 3 h. Afterfiltration, the filtrate was concentrated in vacuo and dried under highvacuum to give the desired product as a solid. LC-MS (M+H) 155.2 (base).

Step 4

The title compound was prepared using the BOP coupling method that wasoutlined in the synthesis of example 1. LC/MS (M+H) 333.2 (base).

Example 2721′-{[1-(4-Methylphenyl)cyclopropyl]carbonyl}spiro[pyrido[3,4-d][1,3]oxazine-4,3′-pyrrolidin]-2(1H)-oneStep 1. benzyl3-{3-[(tert-butoxycarbonyl)amino]pyridin-4-yl}-3-hydroxypyrrolidine-1-carboxylate

To a flame-dried round bottomed flask with thermometer side-arm,equipped with a stir bar, was added tert-butyl pyridin-3-ylcarbamate(1.104 g, 0.005684 mol) in 75 mL THF under inert atmosphere. Thesolution was cooled to −78° C. and then 1.7 M of tert-butyllithium inpentane (7.4 mL) was added dropwise. The resulting solution was stirredfor 2 h at −78° C., followed by the addition of benzyl3-oxopyrrolidine-1-carboxylate (1.038 g, 0.004736 mol) in 75 mL THF. Thereaction was allowed to warm to rt and stirred for 5 hrs. The reactionmixture was quenched with saturated ammonium chloride, diluted withwater and extracted with ethyl acetate. The combined organic phases weretreated with brine and then magnesium sulfate, filtered, andconcentrated. The crude product was purified by combiflash using 50-80%ethyl acetate/hexane to recover the starting material (0.9 g) and then100% ethyl acetate to obtain the product (0.5 g). The product wasverified by LCMS and NMR data.

Step 2. benzyl3-(3-aminopyridin-4-yl)-3-hydroxypyrrolidine-1-carboxylatebis(trifluoroacetate) (salt)

To a stirred solution of benzyl3-{3-[(tert-butoxycarbonyl)amino]pyridin-4-yl}-3-hydroxypyrrolidine-1-carboxylate(4.38 g, 0.0106 mol) in methylene chloride (12.00 mL, 0.1872 mol) at rtwas added trifluoroacetic acid (10.00 mL, 0.1298 mol) and the reactionmixture was stirred at rt for 4 h. LCMS (m+1, 314.2) indicated that thereaction was complete. The volatiles were removed and NMR data supportedthe formation of the desired product.

Step 3. benzyl2-oxo-1,2-dihydro-1′H-spiro[pyrido[3,4-d][1,3]oxazine-4,3′-pyrrolidine]-1′-carboxylate

To a solution of benzyl3-(3-aminopyridin-4-yl)-3-hydroxypyrrolidine-1-carboxylatebis(trifluoroacetate) (salt) (0.4239 g, 0.0007830 mol) in 4 mL THF wasadded triethylamine (0.4365 mL, 0.003132 mol) at 0° C. Then a solutionof triphosgene (0.2323 g, 0.0007830 mol) in 3 mL THF was added rapidly.The mixture was stirred and monitored by LCMS for 45 min at 0° C. After4 h the reaction was quenched with saturated sodium bicarbonate and theproduct was extracted with ethyl acetate. The combined organic phaseswere treated with brine and then magnesium sulfate, filtered, andconcentrated. The crude product was purified by Combiflash.

Step 4. spiro[pyrido[3,4-d][1,3]oxazine-4,3′-pyrrolidin]-2(1H)-one

To a solution of benzyl2-oxo-1,2-dihydro-1′H-spiro[pyrido[3,4-d][1,3]oxazine-4,3′-pyrrolidine]-1′-carboxylate(461.00 mg, 0.0013585 mol) in dichloromethane (10.00 mL, 0.1560 mol) andmethanol (10 mL, 0.2 mol) was added palladium (92 mg, 0.00086 mol). Thereaction was stirred under a hydrogen atmosphere using a balloon for 2h. The reaction mixture was filtered and concentrated to afford theproduct (quantitative yield).

Step 5

The title compound was prepared by a BOP mediated coupling reactionanalogous to that outlined in the synthesis of example 1.

Example 2731-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-3-pyridin-4-ylpyrrolidin-3-olStep 1. tert-butyl 3-hydroxy-3-pyridin-4-ylpyrrolidine-1-carboxylate

1.600 M of n-Butyllithium in hexane (0.810 mL) was added to a solutionof 4-bromopyridine hydrochloride (210 mg, 1.1 mmol) in ether (5 mL, 0.05mol) at −78° C. The solution was stirred at −78° C. for 30 min. and thentert-butyl 3-oxopyrrolidine-1-carboxylate (200 mg, 0.001 mol) was addedand the temperature was maintained at −78° C. for 3 hours. The reactionmixture was quenched with water, extracted with AcOEt. The organic layerwas dried with MgSO₄, and concentrated to afford the desired product.

Step 2. 3-pyridin-4-ylpyrrolidin-3-ol

To the above compound was added hydrogen chloride in 1,4-dioxane (4M, 1mL) and. The mixture was stirred at rt for 2 hours and then concentratedto afford the product.

Step 3

The title compound was prepared using a BOP mediated coupling procedureanalogous to that described for the synthesis of example 1.

Example 2741-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-3-(3-fluoropyridin-4-yl)pyrrolidin-3-ol

This compound was prepared by using an analogous procedure to thatoutlined above for the synthesis of example 273. LC/MS (M+H) 361.7.

Example 2751-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-3-(2-fluorophenyl)pyrrolidin-3-ol

This compound was prepared by using an analogous procedure to thatoutlined above for the synthesis of example 273. LC/MS (M+H) 360.7.

Example 2761-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-3-[2-(hydroxymethyl)phenyl]pyrrolidin-3-ol

This compound was prepared by using an analogous procedure to thatoutlined above for the synthesis of example 273. LC/MS (M+H) 372.7.

Example 2771-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-3-pyridin-2-ylpyrrolidin-3-ol

This compound was prepared by using an analogous procedure to thatoutlined above for the synthesis of example 273.

Example 278(1R)-1′-({1-[4-(Pyrrolidin-1-ylmethyl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-oneStep 1. 1-(4-vinylphenyl)cyclopropanecarbonitrile

A mixture of (4-vinylphenyl)acetonitrile (2.1 g, 0.015 mol),1-bromo-2-chloro-ethane (1.4 mL, 0.016 mol) and benzyltriethylammoniumchloride (0.2 g, 0.0008 mol) in aqueous sodium hydroxide solution (20 m,6 mL) was stirred at 70° C. for 1 h. The reaction mixture was cooled,diluted with water and extracted with ethyl ether. The combined etherlayers were washed with water and brine, dried and concentrated toafford the product.

Step 2. 1-(4-formylphenyl)cyclopropanecarbonitrile

Ozone was bubbled through a solution of1-(4-vinylphenyl)cyclopropanecarbonitrile (1.8 g, 0.011 mol) inmethylene chloride (40 mL, 0.6 mol) at −78° C. until a blue colorappeared and then nitrogen was bubbled through the solution for 10minutes. Methyl sulfide was added and the mixture was stirred overnight.The mixture was washed with water and brine successively, dried, andconcentrated to give the desired product.

Step 3. 1-[4-(pyrrolidin-1-ylmethyl)phenyl]cyclopropanecarbonitrile

A mixture of 1-(4-formylphenyl)cyclopropanecarbonitrile (0.30 g, 0.0018mol), pyrrolidine (0.18 mL, 0.0021 mol) and sodium triacetoxyborohydride(0.74 g, 0.0035 mol) in methanol (5.0 mL, 0.12 mol) was stirred at rtfor 1 h. The reaction was adjusted to be basic (pH=12) and extractedwith ethyl acetate. The combined extract was washed with brine, dried,and concentrated to provide the desired product. LC-MS: 227.1 (M+H)+

Step 4. 1-[4-(pyrrolidin-1-ylmethyl)phenyl]cyclopropanecarboxylic acid

A solution of1-[4-(pyrrolidin-1-ylmethyl)phenyl]cyclopropanecarbonitrile (100 mg,0.0004 mol) in ethanol (5 mL, 0.08 mol) and 50% NaOH (aq. 4 ml) andwater (2 ml) was stirred at 100 celsius overnight. The mixture was thencarefully adjusted to be slightly acidic (pH=6) and the precipitateformed was filtered and dried to afford the product. LC-MS: 246.1 (M+H)+

Step 5

The title compound was prepared using a procedure analogous to that usedfor the synthesis of example 173.

Example 2806-Chloro-1′-({1-[4-(Trifluoromethyl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using an analogous procedure to thatdescribed above for the synthesis of example 232. LC/MS: 437.6 (M+H⁺).

Example 2816-Chloro-1′-{[1-(4-methylphenyl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using an analogous procedure to thatdescribed above for the synthesis of example 232. LC/MS: 383.6 (M+H⁺).

Example 282(1R)-1′-({1-[4-(3-Thienyl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using an analogous procedure to thatdescribed above for the synthesis of example 116. LC/MS: 416.3 (M+H⁺).

Example 2831-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-3-(1,3-thiazol-2-yl)pyrrolidin-3-ol

This compound was prepared by using analogous procedures to thoseoutlined above in steps 1 and 4 of example 269. LC/MS (M+H) 349.1alcohol.

Example 284(1R)-1′-{[1-(2-Naphthyl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-oneStep 1. 1-(2-naphthyl)cyclopropanecarboxylic acid

Sodium hydroxide (50% aqueous solution, 3.20 g, 0.0552 mol) was added toa mixture of 2-naphthylacetonitrile (0.913 g, 0.00546 mol),benzyltriethylammonium chloride (0.09 g, 0.0004 mol), and1-bromo-2-chloro-ethane (1.58 g, 0.0110 mol) at 50 celsius for 5 h. Then1,2-ethanediol (10.0 mL, 0.179 mol) was added and the mixture was heatedat 100° C. overnight. The mixture was poured into ice-water (30 mL) andwas extracted with ethyl ether (2×10 mL). The aqueous phase wasacidified (pH=2) with 1N HCl and was extracted with ethyl acetate (4×15mL). The combined organic phase was washed with brine (10 mL), driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Theresidue was the desired product, which was directly used in next stepreaction without further purification.

Step 2

The title compound was prepared by using an analogous procedure to thatused for the synthesis in step B of example 95. LC/MS: 385.1 (M+H⁺).

Example 285(1R)-1′-({1-[4-(Pyridin-4-ylmethoxy)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared using a procedure analogous to that describedfor the synthesis of example 215. LC/MS: 442.2 (M+H⁺) and 464.1 (M+Na⁺).

Example 286(3aR,7aS)-2-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}octahydro-1H-isoindole

This compound was prepared using an analogous procedure to that used forthe synthesis of example 1. LC/MS (M+H) 304.1.

Example 2871′-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}spiro[isochromene-3,3′-pyrrolidin]-1(4H)-oneStep 1. Benzyl1-oxo-1,4-dihydro-1H-spiro[isochromene-3,3′-pyrrolidin]-1′-carboxylate

Into a 1-neck round-bottom flask were addedN,N-diethyl-2-methylbenzamide (200 mg, 0.001 mol) and anhydrous THF (ca.20 mL) and the solution was cooled to −78° C. prior to the dropwiseaddition of 1.8 M of lithium diisopropylamide in heptane (630 μL). Thecolor changed to purple, which is characteristic of laterally lithiatedspecies due to the ortho-quinodimethane structure. The laterallylithiated species was allowed to form for 40 min. and then a solution ofbenzyl 3-oxopyrrolidine-1-carboxylate (210 mg, 0.00095 mol) in anhydrousTHF (2 mL) was added dropwise via cannula. The color remained indicatingthat there was excess lithiated species. After stirring for 2 h, thereaction was quenched by addition of sat'd. NH₄Cl and the reactionmixture was allowed to gradually warm to rt. The mixture was dilutedwith H₂O (5 mL) and the product was extracted with EtOAc (3×5 mL). Thecombined organic phase was washed with H₂O (5 mL) and brine (5 mL)successively, dried (over Na₂SO₄), filtered, and concentrated in-vacuo.The LC/MS data suggested that a mixture of cyclized and uncyclizedproducts was formed. The crude product was dissolved in toluene andrefluxed overnight in the presence of a catalytic amount ofp-Toluenesulfonic acid monohydrate (159 mg, 0.000836 mol) LC/MS: 411.1(M+H⁺). The product was purified using Combiflash eluting with 30 to 50%EtOAc/hexanes. LC/MS: 360.1 (M+Na⁺).

Step 2. Cbz deprotection

Benzyl1-oxo-1,4-dihydro-1′H-spiro[isochromene-3,3′-pyrrolidine]-1′-carboxylate(10 mg, 0.00003 mol) was dissolved in MeOH. To this solution was addedPd/C Palladium (10 mg, 0.000009 mol) and the reaction vessel was sealedand flushed with N₂ (g) followed by H₂ (g) and then placed under a H₂(g) balloon for 1 h. The palladium was filtered off and the solvent wasremoved from the filtrate. The crude material was used directly in thenext step. LC/MS: 204.3 (M+H⁺).

Step 3

The title compound was prepared using an analogous procedure to thatdescribed for the synthesis of example 1. LC/MS: 382.0 (M+H⁺).

Example 288N-(tert-Butyl)-2-(1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}-3-hydroxypyrrolidin-3-yl)benzenesulfonamideStep 1. 1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}pyrrolidin-3-ol

3-Pyrrolidinol (1.81 g, 0.0208 mol) was added to a mixture of1-(4-chlorophenyl)cyclopropanecarboxylic acid (3.93 g, 0.0200 mol),benzotriazol-1-yloxytris(dimethylamino) phosphonium hexafluorophosphate(8.84 g, 0.0200 mol) and 4-methylmorpholine (9.00 mL, 0.0819 mol) inN,N-dimethylformamide (20.0 mL, 0.258 mol). The mixture was stirred atrt overnight. The mixture was diluted with ethyl acetate (100 mL) andwas washed with NaHCO₃ (7.5%, 3×30 mL). The organic layer was dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas used directly in the next step without further purification.

Step 2. 1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}pyrrolidin-3-one

To a solution of1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}pyrrolidin-3-ol (2.70 g,0.0102 mol) in acetone (50 mL, 0.7 mol) was added Jones oxidant in water(8.00M, 1.90 mL) at 0° C. The solution was stirred at rt for 1 hour andthen Metered, concentrated. The residue was dissolved in AcOEt, and thesolution was washed with water and brine successively, dried over MgSO₄,and concentrated. The crude product was purified using Combiflasheluting with 50% AcOEt in hexanes.

Step 3

To a solution of N-(tert-butyl)benzenesulfonamide (569 mg, 0.00267 mol)in ether (10 mL, 0.1 mol) was added 1.7 M of tert-butyllithium inpentane (4.7 mL) under nitrogen at −78° C. The mixture was stirred at−78° C. for 15 minutes, then at 0° C. for 1 hour. The reaction mixturethen was cooled down to −78° C. again and a solution of1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}pyrrolidin-3-one (640 mg,0.0024 mol) in ether was added. After stirring for 2 hours, the reactionmixture was quenched with saturated NH₄Cl aqueous solution and thenextracted with EtOAc. The combined organic layer was washed with brine,dried over MgSO₄ and concentrated. The crude product was purified usingCombiflash eluting with 30% AcOEt in hexanes to afford the desiredproduct. LC/MS (M+H⁺) 478.0.

Example 2892-[(1-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-3-hydroxypyrrolidin-3-yl)methyl]nicotinicacid

To a solution of 2,2,6,6-tetramethyl-piperidine (0.123 g, 0.000872 mol)in tetrahydrofuran (3.00 mL, 0.0370 mol) at −75° C. was added 2.50 M ofn-butyllithium in hexane (0.500 mL). After stirring for 15 min., asuspension of 2-methylnicotinic acid (120.5 mg, 0.0008787 mol) in THF(5.0 mL) was added at −55° C. The mixture was stirred at −55° C. for 1h. 1-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}pyrrolidin-3-one (100.0mg, 0.0003792 mol, prepared in steps 1 and 2 of example 288) was addedto the above mixture and the reaction temperature was maintained at −50to −40° C. The mixture was stirred at −40° C. for 30 minutes, thenslowly warmed up to 0° C. To the mixture was added acetic acid (0.50 mL,0.0088 mol) at 0° C. and the reaction mixture was stirred overnightwhile gradually warming to rt. The reaction mixture was carefullyneutralized with NaHCO₃ and the resulting mixture was extracted withAcOEt (4×30 mL). The combined organic layer was washed with brine (30mL), dried over MgSO₄, and concentrated. The residue was purified byCombiflash with ethyl acetate/hexane to give the desired product. LC/MS(M+H) 401.7.

Example 2901-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-3-phenylpyrrolidine-3,4-diol

To a solution of1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}-3-phenyl-2,5-dihydro-1H-pyrrole(80 mg, 0.0002 mol, prepared using a procedure analogous to thatdescribed in example 1) in acetone (500 μL, 0.007 mol), water (1250 μL,0.0694 mol), and tert-butyl alcohol (250 μL, 0.0026 mol), was addedosmium tetraoxide (80 mg, 0.00001 mol) followed by 4-methylmorpholine4-oxide (29 mg, 0.00025 mol). The mixture was heated at 70° C. for 1hour. After cooling, it was filtered and the filtrate was purified withprep-HPLC to afford the product (36.5 mg). LCMS: m/z 358.0 (M+H)⁺; 379.9(M+Na⁺).

Example 291(1R)-1′-{[1-(2-Fluoro-4-pyridin-4-ylphenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

To a solution of(1R)-1′-{[1-(4-bromo-2-fluorophenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one(30 mg, 0.00007 mol, this compound was prepared by using a method thatwas analogous to that used for the synthesis of 238) in tetrahydrofuran(0.2 mL, 0.002 mol) were added tris(dibenzylideneacetone)dipalladium(0)(3 mg, 0.000003 mol), ti-tert-butylphosphine (1.7 mg, 0.0000083 mol),4-(tributylstannyl)pyridine (30.7 mg, 0.0000835 mol), and the mixturewas heated to 120° C. under microwave for 30 minutes. The reactionmixture was then filtered and the filtrate was diluted with methanol,and the product was isolated and purified by prep-HPLC. LC/MS (M+H⁺)429.2.

Example 2925-Methoxy-1′-{[1-(4-methylphenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-oneStep 1. tert-butyl5-methoxy-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidine]-1′-carboxylate

A solution of 2-bromo-5-methoxybenzoic acid (1.85 g, 0.00801 mol) intetrahydrofuran (50 mL, 0.6 mol) was cooled below −20° C. under N₂atmosphere and dibutylmagnesium in heptane (1.0 M, 4.2 mL) was slowlyadded to the solution. Then to the mixture was added slowlyn-butyllithium in hexane (2.5 M, 3.5 mL). After stirring below at −15°C. for 1 hour, a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate(1.50 g, 0.00810 mol) in THF (20.0 mL) was added. After stirring below−20° C. for 1 hour, the reaction was quenched with acetic acid (10 mL).The resulting mixture was stirred at rt overnight. The mixture wasneutralized and extracted with EtOAc. The organic layer was washed withNaHCO₃ solution, water and brine successively, dried over Na₂SO₄, andfiltered. The filtrate was concentrated to afford the desired product.LC/MS (M+H⁺) 320.1.

Step 2

A mixture of tert-butyl5-methoxy-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidine]-1′-carboxylate(80.0 mg, 0.000250 mol) and 4M HCl in dioxane was stirred for 2 hoursand then concentrated. To a solution of1-(4-methylphenyl)cyclopropanecarboxylic acid (44.1 mg, 0.000250 mol) indichloromethane (2 mL, 0.03 mol) was added the above residue. Thesolution was cooled to 0° C. and BOP was added. The solution was stirredfor 3 min and then DIEA was added. The solution was stirred at 0° C. for20 min and then gradually allowed to warm to rt with stirring overnight.The crude product was purified using prep-HPLC. LC/MS (M+H⁺) 378.1.

Example 2931′-{[1-(4-Methylphenyl)cyclopropyl]carbonyl}-3-oxo-3H-spiro[2-benzofuran-1,3′-pyrrolidine]-5-carbonitrile

This compound was prepared by using an analogous procedure to that usedfor the synthesis of example 292. LC/MS (M+H⁺) 373.1.

Example 294(1R)-1′-({1-[3′-(Hydroxymethyl)biphenyl-4-yl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 250. LC/MS: 440.2 (M+H⁺).

Example 295(1R)-1′-({1-[2′-(Methylthio)biphenyl-4-yl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 250. LC/MS: 456.2 (M+H⁺).

Example 2961′-{[1-(1,3-Benzothiazol-2-yl)cyclopropyl]carbonyl}-7H-spiro[furo[3,4-b]pyridine-5,3′-pyrrolidin]-7-one

The starting material 1-(1,3-benzothiazol-2-yl)cyclopropanecarboxylicacid was prepared by using a procedure analogous to that in step 1 ofexample 238. The starting material7H-spiro[furo[3,4-b]pyridine-5,3′-pyrrolidin]-7-one hydrochloride wasprepared by using a procedure analogous to that used in step 1 ofexample 90. The amine and carboxylic acid were subjected to BOP mediatedcoupling conditions analogous to those described in step 5 of example82. LC/MS: 392.1 (M+H⁺).

Example 2971′-{[1-(2-Naphthyl)cyclopropyl]carbonyl}-7H-spiro[furo[3,4-b]pyridine-5,3′-pyrrolidin]-7-one

The starting material 1-(2-naphthyl)cyclopropanecarboxylic acid wasprepared by using a procedure analogous to that used in step 1 ofexample 238. The starting material7H-spiro[furo[3,4-b]pyridine-5,3′-pyrrolidin]-7-one hydrochloride wasprepared by using a procedure analogous to that in step 1 of example 90.The amine and carboxylic acid were subjected to BOP mediated couplingconditions analogous to those described in step 5 of example 82. LC/MS:385.1 (M+H⁺).

Example 2981′-({1-[4-(Difluoromethoxy)phenyl]cyclopropyl}carbonyl)-7H-spiro[furo[3,4-b]pyridine-5,3′-pyrrolidin]-7-one

The starting material1-[4-(difluoromethoxy)phenyl]cyclopropanecarboxylic acid was prepared byusing a procedure analogous to that in step 1 of example 238. Thestarting material 7H-spiro[furo[3,4-b]pyridine-5,3′-pyrrolidin]-7-onehydrochloride was prepared by using a procedure analogous to that instep 1 of example 90. The amine and carboxylic acid were subjected toBOP mediated coupling conditions analogous to those described in step 5of example 82. LC/MS: 401.1 (M+H⁺).

Example 299(1R)-1′-{[1-(4-{[4-(Trifluoromethoxy)benzyl]oxy}phenyl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared using a procedure analogous to that describedin steps 1 & 2 of example 104. LC/MS: 525.2 (M+H⁺).

Example 300(1R)-1′-[(1-{4-[1-(4-Bromophenyl)ethoxy]phenyl}cyclopropyl)carbonyl]-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared using a procedure analogous to that describedin example 105. LC/MS: 534.1 (M+H⁺).

Example 301(1R)-1′-{[1-(4-Pyridin-3-ylphenyl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared using a procedure that was analogous to thatdescribed in steps 1 & 2 of example 250. LC/MS: 412.2 (M+H⁺).

Example 302(1R)-4-[4-(4-{1-[(3-Oxo-1′H,3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-1′-yl)carbonyl]cyclopropyl}phenyl)-1,3-thiazol-2-yl]acetonitrile

This compound was prepared using a procedure that was analogous to thatin steps 1-5 of example 142 (replacing thiourea with2-cyanoethanethioamide in step 3). LC/MS: 457.1 (M+H⁺).

Example 303(1R)-1′-({1-[4-(2-Pyridin-3-yl-1,3-thiazol-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared using a procedure that was analogous to thatdescribed in steps 1-5 of example 142 (replacing thiourea withpyridine-3-carbothioamide in step 3). LC/MS: 495.2 (M+H⁺).

Example 304(1R)-1′-({1-[4-(1-Propionyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared using a procedure that was analogous to thatdescribed in steps 1-6 of example 210. LC/MS: 472.2 (M+H⁺).

Example 305 Ethyl4-[4-(1-{[(1R)-3-oxo-1′H,3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate

This compound was prepared using a procedure that was analogous to thatdescribed in steps 1-6 of example 210. LC/MS: 488.2 (M+H⁺).

Example 306(1R)-4-[(E)-2-(4-{1-[(3-Oxo-1′H,3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-1′-yl)carbonyl]cyclopropyl}phenyl)vinyl]benzonitrile

This compound was prepared using a procedure that was analogous to thatdescribed in example 122. LC/MS: 462.2 (M+H⁺).

Example 307(1R)-1′-{[1-(2-Fluoro-4-pyridin-4-ylphenyl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared using a procedure that was analogous to thatdescribed in example 291. LC/MS: 430.2 (M+H⁺).

Example 308(1R)-1′-[(1-{2-Fluoro-4-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}cyclopropyl)carbonyl]-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared using a procedure that was analogous to thatdescribed in example 126. LC/MS: 487.2 (M+H⁺).

Example 309(1R)-1′-({1-[4-(2H-Indazol-2-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared using a procedure that was analogous to thatdescribed in example 129. LC/MS: 451.2 (M+H⁺).

Example 310(1R)-1′-({1-[4-(3,3-Difluoropyrrolidin-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed in example 98, with the exception that the coupling steps werereversed, i.e.,(1R)-1′-{[1-(4-bromophenyl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-onewas prepared first by the BOP mediated coupling reaction and thensubsequently coupled in the presence of Pd(dppf) to3,3-difluoropyrrolidine hydrochloride. LC/MS: 440.2 (M+H⁺).

Example 311(1R)-1′-({1-[2-Fluoro-4-(2-oxopyrrolidin-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-oneStep 1.1′-{[1-(4-bromo-2-fluorophenyl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared using a procedure analogous to that describedin steps 1-2 of example 95. LC/MS: 430.1 & 432.1 (M+H⁺).

Step 2

The title compound was prepared by using a copper (I) mediated couplingreaction analogous to that described in step 1 of example 102. LC/MS:436.2 (M+H⁺).

Example 312(1R)-1′-({1-[4-(2-Oxopyrrolidin-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared using a procedure analogous to that describedin example 98. LC/MS: 418.1 (M+H⁺).

Example 313(1R)-1′-({1-[4-(2-Oxo-1,3-oxazolidin-3-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared using a procedure analogous to that describedin example 102. LC/MS: 420.1 (M+H⁺).

Example 314(1R)-1′-[(1-{4-[(4S)-4-Isopropyl-2-oxo-1,3-oxazolidin-3-yl]phenyl}cyclopropyl)carbonyl]-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

To a solution of(1R)-1′-{[1-(4-bromophenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one(20.0 mg, 0.0000485 mol, prepared by using a procedure analogous to thatused in example 238) and (4S)-4-isopropyl-1,3-oxazolidin-2-one (18.8 mg,0.000146 mol) in freshly distilled toluene (0.34 mL, 0.0032 mol) wereadded tris(dibenzylideneacetone)dipalladium(0) (4.4 mg, 0.0000048 mol),tri-tert-butylphosphine (2.0 mg, 0.0000097 mol) and cesium carbonate(15.8 mg, 0.0000485 mol), and the mixture was heated to at 50° C.overnight. The reaction mixture was then cooled to rt, filtered overcelite and concentrated under reduced pressure. The crude product waspurified by prep-HPLC separation. LC/MS: 462.2 (M+H⁺).

Example 315(1R)-1′-({1-[4-(2-Oxoimidazolidin-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 314. LC/MS: 419.2 (M+H⁺).

Example 316(1R)-1′-({1-[4-(2-Oxoimidazolidin-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 314. LC/MS: 418.2 (M+H⁺).

Example 317(1R)-1′-[(1-{4-[(4S)-4-Isopropyl-2-oxo-1,3-oxazolidin-3-yl]phenyl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 314. LC/MS: 461.2 (M+H⁺).

Example 318(1R)-1′-({1-[2-Fluoro-4-(2-oxopyrrolidin-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

A mixture of(1R)-1′-{[1-(4-bromo-2-fluorophenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one(10 mg, 0.00002 mol, prepared by methods analogous to those used for thesynthesis of example 238), 2-pyrrolidinone (2.4 mg, 0.000028 mol),copper(I) iodide (0.2 mg, 0.000001 mol), trans-1,2-cyclohexanediamine(0.28 μL, 0.0000023 mol), and potassium carbonate (6.4 mg, 0.000046 mol)in toluene (0.5 mL) and N,N-dimethylformamide (0.5 mL) was microwaveirradiated at 110° C. for 30 minutes. The crude product was purifiedwith prep-HPLC. LCMS: m/z 435.2 (M+H⁺); 457.1 (M+Na⁺).

Example 319(1R)-1′-({1-[2-Fluoro-4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis in example 318. LC/MS: 437.1 (MAT).

Example 320 Methyl3-oxo-4-[4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]piperazine-1-carboxylate

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis in example 259. LC/MS: 490.2 (M+H⁺).

Example 321(1R)-1′-[(1-{6-[4-(Cyclopropylcarbonyl)piperazin-1-yl]pyridin-3-yl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

4-Methylmorpholine (2.0×10⁻¹ μL, 0.00018 mol) was added to a mixture of(1R)-1′-{[1-(6-piperazin-1-ylpyridin-3-yl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one(15 mg, 0.000036 mol, this compound was prepared in a way similar tothat described in example 163), cyclopropanecarboxylic acid (3.4 μL,0.000043 mol) and benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (19 mg, 0.000043 mol) in acetonitrile (0.7 mL, 0.01mol). The reaction mixture was stirred at room temperature overnight.The crude product was purified by prep-LCMS. LC/MS: 487.3 (M+H⁺).

Example 322(1R)-1′-[(1-{6-[4-(Pyridin-4-yloxy)piperidin-1-yl]pyridin-3-yl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

Diethyl azodicarboxylate (3.0×10⁻¹ μL, 0.00019 mol) was added to amixture of(1R)-1′-({1-[6-(4-hydroxypiperidin-1-yl)pyridin-3-yl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-onetrifluoroacetate (salt) (42 mg, 0.000077 mol, example 172), 4-pyridinol(18 mg, 0.00019 mol) and triphenylphosphine (5.0×10⁻¹ mg, 0.00019 mol)in tetrahydrofuran (1.0 mL, 0.012 mol). The reaction mixture was stirredat room temperature overnight. The crude product was purified byprep-LCMS. LC/MS: 511.2 (MAO.

Example 323(1R)-1′-[(1-{6-[(3R)-3-(Pyridin-4-yloxy)pyrrolidin-1-yl]pyridin-3-yl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in example 322 using(1R)-1′-[(1-{6-[(3S)-3-hydroxypyrrolidin-1-yl]pyridin-3-yl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-onetrifluoroacetate (salt), as the starting material. LC/MS: 497.2 (M+H⁺).

Example 324(1R)-1′-({1-[4-(6-Methoxypyridin-3-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in example 123. LC/MS: 441.2 (M+H⁺).

Example 325[4′-(1-{[(1R)-3-Oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)biphenyl-3-yl]acetonitrile

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 123. LC/MS: 449.2 (M+H⁺).

Example 326(1R)-1′-({1-[4-(6-Aminopyridin-3-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 250. LC/MS: 426.1 (M+H⁺).

Example 327(1R)-1′-({1-[4-(6-Hydroxypyridin-3-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

A mixture of(1R)-1′-({1-[4-(6-fluoropyridin-3-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one(20.0 mg, 0.0000467 mol, see example 250 for the preparation), andammonium acetate (0.0216 g, 0.000280 mol) in dimethyl sulfoxide (0.5 mL,0.007 mol) and water (0.1 mL) was heated at 100° C. in a sealed tubeovernight. The major product was the phenol rather than the anilinederivative. The product was isolated and purified by prep-HPLC. LC-MS:427.2 (M+H⁺)

Example 328(1R)-1′-({1-[4-(5-Methylpyridin-2-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

To a solution of(1R)-1′-{[1-(4-bromophenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one(20 mg, 0.00005 mol, prepared as example 238) in 1,4-dioxane (0.2 mL,0.002 mol) were added tris(dibenzylideneacetone)dipalladium(0) (0.2 mg,0.0000002 mol), tri-tert-butylphosphine (0.12 mg, 5.8×10⁻⁷ mol),potassium fluoride (9.3 mg, 0.00016 mol) and 2-bromo-5-methylpyridine(0.012 g, 0.000073 mol), and the mixture was heated at 110° C. for 30minutes. The reaction mixture was filtered and the filtrate was dilutedwith methanol. The product was isolated and purified with prep-HPLC.LC-MS: 425.2 (M+H⁺).

Example 329(1R)-1′-[(1-{4-[(Pyridin-2-yloxy)methyl]phenyl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

To a mixture of(1R)-1′-({1-[4-(hydroxymethyl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one(16.0 mg, 0.0000440 mol, prepared in example 237), triphenylphosphine(17 mg, 0.000066 mol), and 2-hydroxypyridine (4.0 mg) in tetrahydrofuran(2 mL, 0.02 mol) was added diisopropyl azodicarboxylate (14 μL, 0.000070mol) at room temperature, and the mixture was stirred overnight. Theproduct was isolated and purified by prep-HPLC. LC-MS: 441.2 (M+H⁺)

Example 330(1R)-1′-[(1-{4-[(Pyridin-3-yloxy)methyl]phenyl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 329. LC/MS: 441.2 (M+H⁺).

Example 331(1R)-1′-[(1-{4-[(Pyridin-4-yloxy)methyl]phenyl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 329. LC/MS: 441.2 (M+H⁺).

Example 3323-(1-{[(1R)-3-Oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)benzonitrile

A mixture of(1R)-1′-{[1-(3-bromophenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one(30 mg, 0.00007 mol, prepared by using a procedure that was analogous tothat used for the synthesis of example 238), zinc cyanide (8.5 mg,0.000073 mol), and tetra-N-butylammonium bromide (5.9 mg, 0.000018 mol)in N,N-dimethylformamide (0.5 mL, 0.006 mol) was microwave irradiated(at 170° C.) for 5 minutes. The crude product was isolated and purifiedwith prep-HPLC. LCMS: m/z 359.1 (M+H⁺).

Example 333(1R)-1′-[(1-Biphenyl-3-ylcyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 244. LC/MS: 410.1 (M+H⁺) & 432.1(M+Na⁺).

Example 334(1R)-1′-{[1-(1-Naphthyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in example 238, starting with methyl-1-naphthaleneacetate.LC/MS: 384.1 (M+H⁺)

Example 335(1R)-1′-[(1-Quinolin-6-ylcyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 238. LC/MS: 385.2 (M+H⁺).

Example 336(1R)-1′-[(1-{4-[(5-Methylisoxazol-3-yl)methoxy]phenyl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 114. LCMS: m/z 445.2 (M+H)⁺; 467.2(M+Na)+

Example 337(1R)-1′-({1-[4-(2-Pyridin-3-yl-1,3-thiazol-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 142. LCMS: m/z 494.2 (M+H)+

Example 338(1R)-1′-[(1-{4-[5-(Trifluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-oneStep 1.(1R)-1′-({1-[4-(1H-tetrazol-5-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

A mixture of4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)benzonitrile(50.0 mg, 0.000140 mol, example 236), sodium azide (109 mg, 0.00167 mol)and ammonium chloride (89.6 mg, 0.00167 mol) in anhydrousN,N-dimethylformamide (1.4 mL, 0.018 mol) in a microwave vial wasirradiated with microwaves to 150° C. for 30 minutes. LCMS showed about60% conversion. The reaction mixture was then irradiated with microwavesto 180° C. for 20 minutes. LCMS showed the reaction was complete. Thereaction mixture was filtered. The filtrate was in prep-HPLC to give theproduct as a colorless solid (44.5 mg, 80% in yield). (M+H⁺)=402.1.

Step 2

A suspension of (1R)-1′-({1-[4-(1H-tetrazol-5-yl)phenyl]cyclopropylcarbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (30.0 mg,0.0000747 mol) in trifluoroacetic anhydride (0.50 mL, 0.0035 mol) in asealed tube was heated at 100° C. for 1 hour with stirring. LCMS showedthe reaction was complete. The product from the reaction mixture wasisolated and purified by prep-HPLC as a colorless solid (24.0 mg, 68% inyield). (M+H⁺)=470.1.

Example 339(1R)-1′-{[1-(4-tert-Butyl-1,3-thiazol-2-yl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 238. LCMS: m/z 397.1 (M+H⁺)

Example 340(1R)-1′-({1-[4-(4-Chlorophenyl)-1,3-thiazol-2-yl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 238. LCMS: m/z 451.0 (M+H⁺)

Example 3411′,1″-[1,4-Phenylenebis(cyclopropane-1,1-diylcarbonyl)]bis(3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one)

This compound was prepared by using a procedure analogous to thatoutlined in example 238.

Example 3424-Hydroxy-1′-[(1-quinolin-4-ylcyclopropyl)carbonyl]-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 95. LCMS: m/z 402.1 (M+H⁺)

Example 3434-Methoxy-1′-[(1-quinolin-4-ylcyclopropyl)carbonyl]-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in example 95. LCMS: m/z 416.1 (M+H⁺)

Example 344(1R)-1′-[(1-Pyridin-3-ylcyclobutyl)carbonyl]-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in example 161. LCMS: m/z 349.1 (M+H⁺)

Example 345(1R)-1′-{[1-(4-Chlorophenyl)cyclobutyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 83. LCMS: m/z 382.4 (M+H⁺)

Example 346(5R)-1′-{[1-(4-Chlorophenyl)cyclobutyl]carbonyl}-7H-spiro[furo[3,4-b]pyridine-5,3′-pyrrolidin]-7-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 156. LCMS: m/z 383.1 (M+H⁺)

Example 3471-{([1-(4-Chlorophenyl)cyclopropyl]carbonyl}-4-phenylpyrrolidin-3-olStep 1. benzyl 3-hydroxy-4-phenylpyrrolidine-1-carboxylate

To a solution of benzyl 3-oxo-4-phenylpyrrolidine-1-carboxylate (200 mg,0.0007 mol) in tetrahydrofuran (2.0 mL, 0.025 mol) under a N₂ atmosphereat −78° C. was added L-Selectride® in tetrahydrofuran (1M, 4.1 mL) withstirring. The mixture was stirred at this temperature for 1.5 hours.LCMS indicated that the starting material was consumed and the reactionwas quenched with water. The solution was adjusted to pH ˜6 to 7 and wasextracted with EtOAc. The organic extract was washed with brine, driedover Na₂SO₄, filtered and the filtrate was concentrated. The resultingresidue was purified with Combiflash, eluting with EtOAc/hexane toafford the product (125 mg). LCMS: m/z 298.0 (M+H⁺); 320.0 (M+Na⁺).

Step 2. 4-phenylpyrrolidin-3-ol

A mixture of benzyl 3-hydroxy-4-phenylpyrrolidine-1-carboxylate (125 mg,0.000420 mol), palladium (25 mg, 0.000023 mol) in methanol (10 mL, 0.2mol) was stirred under a H₂ atmosphere (balloon with H2) over 2 hours.LCMS indicated that the starting material was consumed. The reactionmixture was filtered and the filtrate was concentrated to yield theproduct (62 mg). LCMS: m/z 163.9 (M+H⁺).

Step 3

The title compound was prepared by using a procedure analogous to thatoutlined in example 4. LCMS: m/z 342.1 (M+H⁺); 364.1 (M+Na⁺); 707.2(2M+Na⁺) (trans-isomer).

Example 3486-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-1,3,3-trimethyl-6-azabicyclo[3.2.1]octane

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis in example 4. LCMS: m/z 332.6 (M+H)⁺

Example 349((2S,3R)-1-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-3-phenylpyrrolidin-2-yl)methanolStep 1. [(2S,3R)-3-phenylpyrrolidin-2-yl]methanol

Borane in tetrahydrofuran (1.0 M, 1.0 mL) was added to(2S,3R)-3-phenylpyrrolidine-2-carboxylic acid (30.0 mg, 0.000157 mol) intetrahydrofuran (1.0 mL, 0.012 mol) at rt. After stirring for 1 h thesolvent was evaporated under reduced pressure and the residue wasazeotroped with methanol (3×2 mL) to afford the desired product, whichwas directly used in next step reaction without further purification.

Step 2

The title compound was prepared by using a procedure analogous to thatoutlined for the synthesis in example 4. LCMS: m/z 356.6 (M+H)⁺

Example 350((2S,4S)-1-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-4-phenylpyrrolidin-2-yl)methanol

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis in example 4. LCMS: m/z 356.6 (M+H)⁺

Example 351((2S,4R)-1-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-4-phenylpyrrolidin-2-yl)methanolStep 1. Methyl(2S,4R)—N-tert-Butoxycarbonyl-4-hydroxy-2-pyrrolidinecarboxylate

To a suspension of methyl (2S,4R)-4-hydroxypyrrolidine-2-carboxylatehydrochloride (10.00 g, 0.05506 mol) in methylene chloride (50 mL, 0.8mol) was added triethylamine (20 mL, 0.1 mol) at ambient temperature.The reaction mixture was stirred for 15 minutes and then cooled to 0° C.4-Dimethylaminopyridine (0.8 g, 0.007 mol) and di-tert-butyldicarbonate(22.00 g, 0.1008 mol) were added sequentially and the reaction wasallowed to warm slowly to ambient temperature with stirring. Thereaction mixture was filtered to remove the solid and the filtrate wasthen concentrated in vacuo. The residue was dissolved in EtOAc (50 mL)and the solution was washed with 1N HCl (20 mL) and then NaHCO₃ (10 mL)and finally brine. The organic layer was then dried over MgSO₄ andconcentrated in vacuo. The ¹H NMR confirmed the product was formed.

Step 2. 1-tert-butyl 2-methyl (2S)-4-oxopyrrolidine-1,2-dicarboxylate

Methyl (2S,4R)—N-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinecarboxylate(2.00 g, 0.00815 mol) was dissolved in acetone (50.0 mL, 0.681 mol) andether (50 mL). To the solution with stirring, was added a solution ofchromium(VI) oxide (1.90 g, 0.0190 mol) in water (5.50 mL, 0.305 mol)and sulfuric acid (1.60 mL, 0.0294 mol) over 15 minutes with thepresence of an ice-water bath to maintain the reaction temperature atabout room temperature. The mixture was stirred at rt for 10 minutes andthen iso-propanol (10 mL) was added. The mixture was stirred for anadditional 5 min. The mixture was filtered through a pad of silica gelplus potassium carbonate. The filtrated was concentrated and the residuewas purified by Combiflash with ethyl acetate/hexane (25%) to give thedesired product (1.12 g).

Step 3. 1-tert-butyl 2-methyl(2S)-4-hydroxy-4-phenylpyrrolidine-1,2-dicarboxylate

Phenylmagnesium bromide in ether (3.00M, 0.400 mL) was added to asolution of 1-tert-butyl 2-methyl(2S)-4-oxopyrrolidine-1,2-dicarboxylate (243.0 mg, 0.0009989 mol) intetrahydrofuran (5.00 mL, 0.0616 mol) at −40° C. The reaction mixturewas stirred at between −40° C. and −10° C. for 2 h and then was quenchedwith ammonium chloride solution (5 mL). The organic phase was separatedand the aqueous phase was extracted with ethyl acetate (2×5 mL). Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue was useddirectly in the next step without further purification.

Step 4. methyl (2S,4R)-4-phenylpyrrolidine-2-carboxylate

1-tert-Butyl 2-methyl(2S)-4-hydroxy-4-phenylpyrrolidine-1,2-dicarboxylate (0.32 g, 0.0010mol) was treated with trifluoroacetic acid (1.00 mL, 0.0130 mol) andmethylene chloride (1.00 mL, 0.0156 mol) at rt for 4 h. The solventswere evaporated and the residue was dissolved in methanol (5.0 mL, 0.12mol). Palladium (50.0 mg, 0.000470 mol) was added under nitrogen and theresulting mixture was hydrogenized with a hydrogen-gas-filled-balloonfor 3 h. The mixture was filtered and the filtrate was concentrated togive the desired product, which was directly used in the next stepwithout further purification.

Step 5. [(2S,4R)-4-phenylpyrrolidin-2-yl]methanol

Lithium tetrahydroaluminate in tetrahydrofuran (1.00 M, 1.00 mL) wasadded to methyl (2S,4R)-4-phenylpyrrolidine-2-carboxylate (103.0 mg,0.0005018 mol) in tetrahydrofuran (3.00 mL, 0.0370 mol) at 0° C. Thenthe ice-water bath was removed and the reaction mixture was stirred atrt for 1 h and was quenched with brine (1 mL). The resulting mixture wasextracted with ethyl acetate (2×2 mL). The combined organic layer waswashed with brine, dried over Na₂SO_(a), filtered, and concentratedunder reduced pressure to give the desired product which was directlyused in the next step without further purification.

Step 6

The title compound was prepared by using a procedure analogous to thatoutlined for the synthesis in example 4. LCMS: m/z 356.6 (M+H)³⁰

Example 352 1-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}pyrrolidine

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis in example 4. LCMS: m/z 250.4 (M+H)⁺

Example 353 1-{[1-(4-Chlorophenyl)cyclopentyl]carbonyl}azepane

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis in example 4. LCMS: m/z 306.5 (M+H)⁺

Example 3543-Chloro-N-((3S)-1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}pyrrolidin-3-yl)-2-methylbenzenesulfonamideStep 1.tert-butyl((3S)-1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}pyrrolidin-3-yl)carbamate

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis in example 4. LCMS: m/z 365.5 (M+H)⁺

Step 2

tert-Butyl((3S)-1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}pyrrolidin-3-yl)carbamate (7.30 mg, 0.0000200 mol) was treated with hydrogen chloride in1,4-dioxane (4.0 M, 0.50 mL) at rt for 30 minutes. The solvent wasevaporated under reduced pressure and acetonitrile (1.0 mL, 0.019 mol)was added. The mixture was then treated with N,N-diisopropylethylamine(20.0 μL, 0.000115 mol), followed by the addition of3-chloro-2-methylbenzenesulfonyl chloride (4.50 mg, 0.0000200 mol) atrt. The reaction mixture was stirred at rt for 1 h and then acidified(pH=2.0) with TFA. The solution was diluted with methanol (0.80 mL) andwas submitted for purification by prep-HPLC to give the desired product.LCMS: m/z 454.1 (M+H)⁺

Example 355(3S,4R)-1-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-4-phenylpyrrolidine-3-carboxylicacid

To a solution of methyl(3S,4R)-1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}-4-phenylpyrrolidine-3-carboxylate(50 mg, 0.0001 mol, example 39) in tetrahydrofuran (2 mL, 0.02 mol) wasadded lithium hydroxide (9.4 mg, 0.00039 mol) and water (0.5 mL, 0.03mol) and the solution was stirred at rt for 1 h. The reaction mixturewas then acidified (pH ˜2) and was extracted with AcOEt. The organiclayer was dried (over MgSO₄), and concentrated to afford the product.LCMS: m/z 370.4 (M+H)⁺

Example 356((3S,4R)-1-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-4-phenylpyrrolidin-3-yl)methanol

To a solution of(3S,4R)-1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}-4-phenylpyrrolidine-3-carboxylicacid (80 mg, 0.0002 mol, example 355) in tetrahydrofuran (2 mL, 0.02mol) were added triethylamine (0.0316 mL, 0.000227 mol) and methylchloroformate (20.0 μL, 0.000260 mol) at −15° C. The mixture was stirredat −15° C. for 20 minutes. To the above mixture was added sodiumborohydride (16.4 mg, 0.000433 mol) in THF and the resulting mixture wasstirred at 0° C. for 1 h. The reaction mixture was quenched by water andthen was extracted with AcOEt. The organic layer was dried over MgSO₄,and concentrated to afford the product. The product was purified withCombiflash eluting with 60% AcOEt in hexanes. LCMS: m/z 356.4 (M+H)⁺

Example 3572-[1-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-4-(hydroxymethyl)pyrrolidin-3-yl]phenolStep 1. N-Benzyl-N-(trimethylsilyl)methylamine

Into a round bottom 3-neck flask equipped with a nitrogen flow, amagnetic stirrer, and a friedrichs condenser was added(chloromethyl)trimethylsilane (0.100 mol). To the flask was addedbenzylamine (0.300 mol), with stirring, and the resulting solutionheated at 200° C. for 2.5 hours. Sodium hydroxide aqueous solution(0.1N) was added in order to hydrolyze the white organic salt that hadformed. The mixture was extracted with ether and the ether layer wasdried over magnesium sulfate and concentrated under reduced pressurethrough a Vigreux column to give the product at b.p. 68-72° C./0.7-0.8mm.

Step 2. N-Benzyl-N-methoxymethyl-N-(trimethylsilyl)methylamine

Into a round bottom 3-neck flask equipped with a nitrogen flow and amagnetic stirrer was added formaldehyde (74.000 mmol, 7.4000×10⁻² mol)(as a 37% aqueous solution). The flask was cooled to 0° C. andN-benzyl-N-(trimethylsilyl)methylamine (10.000 g, 5.1716790×10⁻² mol)was added dropwise with stirring. After stirring for 10 minutes at 0°C., methanol (6.000 mL, 0.14811874 mol) was added in one portion.Potassium carbonate (4.000 g, 2.8942408×10⁻² mol) was added to themixture to absorb the aqueous phase. The mixture was stirred for onehour, then the nonaqueous phase decanted, and then potassium carbonate(2.000 g, 1.4471204×10⁻² mol) was added. The mixture was stirred at 25°C. for 12 hours. Ether is added to the mixture and the solution wasdried over potassium carbonate, filtered and concentrated under reducedpressure. The residue is distilled at reduced pressure to give theproduct as a colorless liquid.

Step 4. 2-benzyl-2,3,3a,9b-tetrahydrochromeno[3,4-e]pyrrol-4(1H)-one

N-Benzyl-N-methoxymethyl-N-(trimethylsilyl)methylamine (1.54 mL, 0.00600mol) in methylene chloride (0.50 mL) was added to a mixture of coumarin(0.731 g, 0.00500 mol) and of trifluoroacetic acid in DCM (1M, 10 mL) atrt. The resulting mixture was stirred at rt for 1 h and was then washedwith NaHCO₃ (2 mL) and brine (2 mL) successively. The organic phase wasdried (over Na₂SO₄), filtered, and concentrated. The residue waspurified by CombiFlash (ethyl acetate/hexane 20%) to give the desiredproduct (0.99 g).

Step 5. 2-[1-benzyl-4-(hydroxymethyl)pyrrolidin-3-yl]phenol

Lithium tetrahydroaluminate in tetrahydrofuran (1.00 M, 1.50 mL) wasadded to a solution of2-benzyl-2,3,3a,9b-tetrahydrochromeno[3,4-c]pyrrol-4(1H)-one (188.0 mg,0.0006730 mol) in THF (2.0 mL) at 0° C. The mixture was stirred at 0° C.for 1 h and then quenched with acetone. Ethyl acetate (10 mL) was addedand the resulting mixture was treated with NaOH (1N, 3 mL) and then wasfiltered through a pad of celite. The filtrate was washed with brine(2×5 mL) and the organic layer was dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to give the desired product.

Step 6. (cis)-2-[4-(hydroxymethyl)pyrrolidin-3-yl]phenol

A mixture of 2-[1-benzyl-4-(hydroxymethyl)pyrrolidin-3-yl]phenol (101.4mg, 0.0003580 mol) and palladium (10% on carbon, 75 mg) in methanol (5.0mL, 0.12 mol) was stirred under hydrogen (balloon) overnight. Themixture was filtered and the filtrate was concentrated. The residue wasused in next step without further purification.

Step 7

The title compound was prepared by using a procedure analogous to thatoutlined for the synthesis in example 4. LCMS: m/z 372.5 (M+H)⁺

Example 3582-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-1,2,3,3a,4,9b-hexahydrochromeno[3,4-e]pyrrole

A mixture of2-[1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}-4-(hydroxymethyl)pyrrolidin-3-yl]phenol(13.0 mg, 0.0000350 mol), triphenylphosphine (20.0 mg, 0.0000762 mol)and diisopropyl azodicarboxylate (15.0 μL, 0.0000762 mol) intetrahydrofuran (1.0 mL, 0.012 mol) was stirred at rt for 4 h. Themixture was diluted with methanol (0.80 mL) and the desired product fromthe mixture was isolated and purified by prep-HPLC. LCMS: m/z 354.5(M+H)⁺

Example 3592-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-8-(methylsulfonyl)-2,8-diazaspiro[4.5]decaneStep 1. tert-butyl8-(methylsulfonyl)-2,8-diazaspiro[4.5]decane-2-carboxylate

N,N-Diisopropylethylamine (30.0 μL, 0.000172 mol) was added totert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate hydrochloride (18.5mg, 0.0000668 mol) in acetonitrile (1.0 mL, 0.019 mol), followed bymethanesulfonyl chloride (10.0 μL, 0.000129 mol). After stirring for 1 hthe solvent was evaporated, and the residue was dried under high vacuumand was used in the next step without further purification.

Step 2. 8-(methylsulfonyl)-2,8-diazaspiro[4,5]decane hydrochloride

Hydrogen chloride in 1,4-dioxane (4.0M, 0.50 mL) was added to tert-butyl8-(methylsulfonyl)-2,8-diazaspiro[4.5]decane-2-carboxylate (21.0 mg,0.0000659 mol) at rt. The mixture was stirred at rt for 1 h and then thesolvent was evaporated, and the residue was dried under high vacuum toafford the desired product. LCMS: m/z 255.5 (M+H)'

Step 3

The title compound was prepared by using a procedure analogous to thatoutlined for the synthesis in example 4. LCMS: m/z 397.5 (M+H)⁺

Example 3608-Acetyl-2-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}-2,8-diazaspiro[4.5]decane

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis in example 359. LCMS: m/z 361.5 (M+H)⁺

Example 3613-(1-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}pyrrolidin-3-yl)pyridine

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis in example 4. LCMS: m/z 327.5 (M+H)⁺

Example 3623-(1-{[1-(4-Phenoxyphenyl)cyclopropyl]carbonyl}pyrrolidin-3-yl)pyridineStep 1. 4-{1-[(3-pyridin-3-ylpyrrolidin-1-yl)carbonyl]cyclopropyl}

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis in example 4. LCMS: m/z 309.1 (M+H)⁺

Step 2

To a solution of4-{1-[(3-pyridin-3-ylpyrrolidin-1-yl)carbonyl]cyclopropyl}phenol (40.0mg, 0.000130 mol) in methylene chloride (1 mL, 0.02 mol) were addedphenylboronic acid (15.8 mg, 0.000130 mol), copper(II) diacetate (0.0236g, 0.000130 mol) and molecular sieves at rt. Triethylamine (0.0904 mL,0.000648 mol) was then added and the reaction mixture was stirred at rtovernight. The reaction mixture was filtered and the filtrate wasconcentrated. The desired product from the residue was isolated andpurified by prep-HPLC. LCMS: m/z 385.1 (M+H)⁺

Example 3633-[1-({1-[4-(Cyclopentyloxy)phenyl]cyclopropyl}carbonyl)pyrrolidin-3-yl]pyridine

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis in example 4. LCMS: m/z 309.1 (M+H)⁺

Step 2

To a solution of4-{1-[(3-pyridin-3-ylpyrrolidin-1-yl)carbonyl]cyclopropyl}phenol (40.0mg, 0.000130 mol) in tetrahydrofuran were added cyclopentanol (29.4 μL,0.000324 mol) diethyl azodicarboxylate (0.0511 mL, 0.000324 mol), andtriphenylphosphine (85.0 mg, 0.000324 mol) at room temperature, and thereaction mixture was stirred overnight. The crude product was purifiedby prep-HPLC. LCMS: m/z 377.1 (M+H)⁺

Example 364 tert-Butyl4-(5-{1-[(3-pyridin-3-ylpyrrolidin-1-yl)carbonyl]cyclopropyl}pyridine-2-yl)piperazine-1-carboxylate

This compound was prepared by using a procedure analogous to thatoutlined in steps 1-3 of example 163. LCMS: m/z 478.1 (M+H)⁺

Example 3651-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-3-isopropylpyrrolidineStep 1. tert-butyl 3-hydroxy-3-isopropenylpyrrolidine-1-carboxylate

To a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (2.0 g, 0.011mol) in tetrahydrofuran (15.4 mL, 0.190 mol) was added dropwise a 0.5 Min THF solution of bromo(isopropenyl)magnesium (1.80 g, 0.0124 mol)(24.8 mL) at rt under N₂. After the addition was complete, the reactionmixture was heated to reflux for 15 minutes and then cooled to rt. Thecrude mixture was poured into saturated NH₄Cl, extracted with ether (3×)The combined organic phase was dried over MgSO₄, concentrated in vacuo.The crude product was purified by flash chromatography eluting with0-40% EA-hexanes to afford pure product as a white solid (1.4 g). Theproduct was confirmed by ¹H NMR & LC/MS (M+H-Boc) 128.1 (base), [(M+Na)250.0].

Step 2. 3-isopropenyl-2,5-dihydro-1H-pyrrole trifluoroacetate

tert-Butyl 3-hydroxy-3-isopropenylpyrrolidine-1-carboxylate (1.51 g,0.00664 mol) was dissolved in trifluoroacetic acid (10.0 mL, 0.130 mol)under N₂ at rt. The reaction flask was wrapped with aluminum foil andthe mixture was stirred overnight. The reaction mixture was thenconcentrated in vacuo and the residue was used directly in the next stepwithout further purification.

Step 3. 3-isopropylpyrrolidine trifluoroacetate

To a solution of 3-isopropenyl-2,5-dihydro-1H-pyrrole trifluoroacetate(2.09 g, 0.00936 mol) in methanol (100.0 mL, 2.469 mol) was added 1.3 gof Pd (10% wt. on activated carbon), then the mixture was hydrogenatedon par shaker at 43 psi for 3 h. The mixture was filtered and thefiltrate was concentrated in vacuo. The residue was dried under highvacuum to afford the product as a white solid. LC-MS (M+H) 114.2 (base)[M+H) 130.1 base, for the corresponding alcohol].

Step 4

The title compound was prepared by using a procedure analogous to thatoutlined for the synthesis in example 4.

Example 366 Methyl3-(1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}pyrrolidin-3-yl)benzoateStep 1. methyl 3-[1-(phenoxyacetyl)-2,3-dihydro-1H-pyrrol-3-yl]benzoate

A solution of benzyl 2,5-dihydro-1H-pyrrole-1-carboxylate (0.626 mL,0.00349 mol), methyl 3-bromo-benzoate (300 mg, 0.001 mol), palladium(II)diacetate (14 mg, 0.000063 mol), potassium acetate (356 mg, 0.00363mol), and tetra-N-butylammonium bromide (4.50×10⁻² mg, 0.00140 mol) inN,N-dimethylformamide (5 mL, 0.06 mol) was stirred under nitrogen at 40°C. for 4 days. The reaction mixture was diluted with AcOEt and water.The organic layer was separated and the aqueous layer was extracted withAcOEt. The combined organic layer was washed with brine, dried withMgSO₄, and concentrated to afford the crude product. The crude productwas purified by flash chromatography, eluting with 30% AcOEt in hexanes.

Step 2. methyl 3-pyrrolidin-3-ylbenzoate

To a solution of methyl3-[1-(phenoxyacetyl)-2,3-dihydro-1H-pyrrol-3-yl]benzoate (0.5 g, 0.001mol) in methanol (15 mL, 0.37 mol) was added 10% Pd/C (80 mg), and theresulting suspension was stirred under 1 atm of H₂ (balloon) for 5 h.The mixture was filtered and the filtrate was concentrated to afford thedesired product.

Step 3

The title compound was prepared by using a procedure analogous to thatoutlined for the synthesis in example 4. LCMS: m/z 384.4 (M+H)'

Example 3671-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-3-(2-methylphenyl)pyrrolidineStep 1.1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}-3-(2-methylphenyl)-2,5-dihydro-1H-pyrrole

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis in example 4. LCMS: m/z 338.4 (M+H)⁺

Step 2

To a solution of1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}-3-(2-methylphenyl)-2,5-dihydro-1H-pyrrole(5 mg, 0.00001 mol) in methanol (1 mL, 0.02 mol) was added Pd/BaSO₄(reduced) and the mixture was stirred under an atmosphere of hydrogen atrt for 1 h. The crude product was purified using prep-HPLC. LCMS: m/z340.4 (M+H)'

Example 3681-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-3-(2-methoxyphenyl)pyrrolidine

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis in example 367. LCMS: m/z 356.4 (M+H)'

Example 3691-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-3-(2,6-dimethylphenyl)pyrrolidine

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis in example 4. LCMS: m/z 354.4 (M+H)'

Example 3701-(4-{1-[(3-Pyridin-4-ylpyrrolidin-1-yl)carbonyl]cyclopropyl}phenyl)pyrrolidin-2-one

This compound was prepared by coupling the title compound in example 23with 2-pyrrolidinone using a copper mediated procedure analogous to thatoutlined in step 1 of example 102. LCMS: m/z 376.3 (M+H⁺); 398.3(M+Na⁺).

Example 3713-(4-{1-[(3-Pyridin-4-ylpyrrolidin-1-yl)carbonyl]cyclopropyl}phenyl)-1,3-oxazolidin-2-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis in example 370. LCMS: m/z 378.2 (M+H)⁺

Example 3724-{1-[(3-Pyridin-4-ylpyrrolidin-1-yl)carbonyl]cyclopropyl}phenol

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis in example 4. LCMS: m/z 309.0 (M+H)'

Example 3734-[1-({1-[4-(Benzyloxy)phenyl]cyclopropyl}carbonyl)pyrrolidin-3-yl]pyridine

A mixture of4-{1-[(3-pyridin-4-ylpyrrolidin-1-yl)carbonyl]cyclopropyl}phenol (20 mg,0.00006 mol, example 372), benzyl bromide (7.7 μL, 0.000065 mol), andpotassium carbonate (18 mg, 0.00013 mol) in N,N-dimethylformamide (200μL, 0.002 mol) was stirred at room temperature over night. The crudeproduct was purified with prep-HPLC to afford the product (10.3 mg).LCMS: m/z 399.0 (M+H⁺).

Example 3744-[1-({1-[4-(Allyloxy)phenyl]cyclopropyl}carbonyl)pyrrolidin-3-yl]pyridine

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis in example 373. LCMS: m/z 349.1 (M+H)⁺.

Example 3754-[1-({1-[4-(Pyridin-4-yloxy)phenyl]cyclopropyl}carbonyl)pyrrolidin-3-yl]pyridine

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis in example 362. LCMS: m/z 386.1 (M+H)⁺.

Example 3774-[1-({1-[4-(Cyclopentyloxy)phenyl]cyclopropyl}carbonyl)pyrrolidine-3-yl]pyridine

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis in example 373. LCMS: m/z 377.1 (M+H)⁺, 399.0(M+Na)⁺.

Example 3784-[1-({1-[4-(Cyclohex-2-en-1-yloxy)phenyl]cyclopropyl}carbonyl)pyrrolidine-3-yl]pyridine

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis in example 373. LCMS: m/z 411.0 (M+Na)⁺.

Example 3793-[(4-{1-[(3-Pyridin-4-ylpyrrolidin-1-yl)carbonyl]cyclopropyl}phenoxy)methyl]pyridine

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis in example 373. LCMS: m/z 400.1 (M+H)⁺, 422.1(M+Na)⁺.

Example 3802-[(4-{1-[(3-Pyridin-4-ylpyrrolidin-1-yl)carbonyl]cyclopropyl}phenoxy)methyl]pyridine

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis in example 373. LCMS: m/z 400.1 (M+H)⁺, 422.1(M+Na)⁺.

Example 3814-[2-(4-{1-[(3-Pyridin-4-ylpyrrolidin-1-yl)carbonyl]cyclopropyl}phenoxy)ethyl]morpholine

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis in example 214. LCMS: m/z 422.1 (M+H)⁺.

Example 3824-((3S)-1-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}pyrrolidin-3-yl)pyridine1-oxide

4-((3S)-1-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}pyrrolidin-3-yl)pyridine(20 mg, 0.00006 mol, example 24) was dissolved in dichloromethane (1 mL,0.02 mol) and to this solution was added m-chloroperbenzoic acid (44 mg,0.00015 mol). The reaction mixture was stirred at 25° C. for 2.5 h. Thereaction mixture then was concentrated and the residue was diluted withNaHCO₃ and methanol. The crude product was purified by prep-HPLC. LCMS:m/z 343.4 (M+H)⁺.

Example 3834-(1-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}pyrrolidin-3-yl)-3-fluoropyridine

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis in example 4. LCMS: m/z 345.4 (M+H)⁺.

Example 3841-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-3-isopropylpyrrolidin-3-ol

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis in example 365. LCMS: m/z 308.1 (M+H)⁺.

Example 3853-tert-Butyl-1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}pyrrolidine-3-olStep 1. tert-butyl 3-tert-butyl-3-hydroxypyrrolidine-1-carboxylate

To a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (500.0 mg,0.002699 mol) in tetrahydrofuran (3.85 mL, 0.0475 mol) was addeddropwise a 1.7 M in pentane solution of tert-butyllithium (198.8 mg,0.003104 mol) (1.8 mL) at −78° C. under N₂. After the addition wascomplete, the reaction mixture was warmed to rt. After stirring for 1 h,the reaction mixture was poured into a saturated NH₄Cl aqueous solutionand the resulting mixture was extracted with ether (3×). The combinedorganic layer was dried over MgSO₄, and concentrated in vacuo. The crudeproduct was purified by Combiflash eluting with 0-40% EtAc-hexanes toafford the product as a white solid (0.451 g). LC MS (M+H-Boc) 144.1

Step 2. 3-tert-butylpyrrolidin-3-ol hydrochloride

tert-Butyl 3-tert-butyl-3-hydroxypyrrolidine-1-carboxylate (0.60 g,0.0025 mol) was dissolved in a solution of hydrogen chloride in1,4-dioxane (4N, 0.30 mL, 0.0099 mol) under N₂ at rt. The reactionmixture was stirred for 3 h at rt, then concentrated in vacuo. The crudeproduct was used directly in the next step without further purification.(M+H) 144.1

Step 3

The title compound was prepared by using a procedure analogous to thatoutlined for the synthesis in example 4. LCMS: m/z 322.2 (M+H)⁺.

Example 3861-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-3-(2-methylphenyl)pyrrolidin-3-ol

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis in example 273. LCMS: m/z 356.4 (M+H)⁺.

Example 387Methyl[(1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}-3-phenylpyrrolidin-3-yl)oxy]acetateStep 1. tert-butyl 3-hydroxy-3-phenylpyrrolidine-1-carboxylate

To a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (1.0 g,0.0054 mol) in ether (20.000 mL, 0.19050 mol) was added dropwise asolution of phenylmagnesium bromide (1.12 g, 0.00621 mol) in ether (10.3mL) at rt under N₂. After the addition was complete, the reactionmixture was heated to reflux for 15 min. and then cooled to rt. Thereaction mixture was poured into saturated NH₄Cl and extracted withether (3×). The combined organic layers were dried over Na₂SO₄ andconcentrated in vacuo. The product was purified by Combiflash elutingwith 0-40% EtOAc-hexanes. The product was confirmed by ¹H NMR and LC/MS:m/z 286.0 (M+Na)⁺.

Step 2. tert-butyl3-(2-methoxy-2-oxoethoxy)-3-phenylpyrrolidine-1-carboxylate

To a solution of tert-butyl 3-hydroxy-3-phenylpyrrolidine-1-carboxylate(480 mg, 0.0018 mol) in toluene (20 mL, 0.2 mol) was added sodiumhydride (80.2 mg, 0.00200 mol) and the solution was refluxed for 1 hour.Methyl bromoacetate (0.190 mL, 0.00200 mol) was then added and themixture continued to be stirred under reflux overnight. The reactionmixture was allowed to cool to rt and the product was extracted withEtOAc. The combined organic layers were washed with water, dried withMgSO₄, and concentrated in-vacuo. LC/MS: m/z 336.1 (M+H)⁺.

Step 3. Methyl[(3-phenylpyrrolidin-3-yl)oxy]acetate

To tert-butyl3-(2-methoxy-2-oxoethoxy)-3-phenylpyrrolidine-1-carboxylate (160 mg,0.00048 mol) was added 4 M of hydrogen chloride in 1,4-dioxane (1 mL)and the resulting solution was stirred for 1 h. The reaction mixture wasthen concentrated in-vacuo and the crude product was used directly inthe next step.

Step 4.Methyl[(1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}-3-phenylpyrrolidin-3-yl)oxy]acetate

The title compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 4. LCMS: m/z 414.4 (M+H)*.

Example 388[(1-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-3-phenylpyrrolidin-3-yl)oxy]aceticacid

To a solution ofmethyl[(1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}-3-phenylpyrrolidin-3-yl)oxy]acetate(40.0 mg, 0.0000966 mol, example 387) in tetrahydrofuran (1 mL, 0.01mol) was added lithium hydroxide hydrate (4.87 mg, 0.000116 mol) inwater (0.5 mL, 0.03 mol). The solution was stirred at rt for 2 hours andthen acidified with 1N HCl (aq.). The product was purified by prep-HPLC.LCMS: m/z 400.4 (M+H)⁺.

Example 3891-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-3-(3-chloropyridin-4-yl)pyrrolidine-3-ol

This compound was prepared by using a procedure analogous to thatoutlined in example 273. LCMS: m/z 378.1 (M+H)⁺.

Example 3901′-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}spiro[pyrido[3,4-d][1,3]oxazine-4,3′-pyrrolidin]-2(1H)-one

This compound was prepared by using a procedure analogous to thatoutlined in example 272.

Example 3911′-{[1-(2,4-Dichlorophenyl)cyclopropyl]carbonyl}spiro[pyrido[3,4-d][1,3]oxazine-4,3′-pyrrolidin]-2(1H)-one

This compound was prepared by using a procedure analogous to thatoutlined in example 272

Example 3921′-{[1-(4-Bromophenyl)cyclopropyl]carbonyl}spiro[pyrido[3,4-d][1,3]oxazine-4,3′-pyrrolidin]-2(1H)-one

This compound was prepared by using a procedure analogous to thatoutlined in example 272.

Example 3931′-{[1-(4-Methoxyphenyl)cyclopropyl]carbonyl}spiro[pyrido[3,4-d][1,3]oxazine-4,3′-pyrrolidin]-2(1H)-one

This compound was prepared by using a procedure analogous to thatoutlined in example 272.

Example 3941′-{[1-(4-Phenoxyphenyl)cyclopropyl]carbonyl}spiro[pyrido[3,4-d][1,3]oxazine-4,3′-pyrrolidin]-2(1H)-one

This compound was prepared by using a procedure analogous to thatoutlined in example 272.

Example 3951′-[(1-{4-[(Trifluoromethyl)thio]phenyl}cyclopropyl)carbonyl]spiro[pyrido[3,4-d][1,3]oxazine-4,3′-pyrrolidin]-2(1H)-one

This compound was prepared by using a procedure analogous to thatoutlined in example 272.

Example 3961′-{[1-(3-Bromophenyl)cyclopropyl]carbonyl}spiro[pyrido[3,4-d][1,3]oxazine-4,3′-pyrrolidin]-2(1H)-one

This compound was prepared by using a procedure analogous to thatoutlined in example 272.

Example 3971′-{[1-(3-Methoxyphenyl)cyclopropyl]carbonyl}spiro[pyrido[3,4-d][1,3]oxazine-4,3′-pyrrolidin]-2(1H)-one

This compound was prepared by using a procedure analogous to thatoutlined in example 272.

Example 3981′-{[1-(6-Chloropyridin-3-yl)cyclopropyl]carbonyl}-7H-spiro[furo[3,4-b]pyridine-5,3′-pyrrolidin]-7-one

This compound was prepared by using a procedure analogous to thatoutlined in example 90 using1-(6-chloropyridin-3-yl)cyclopropanecarboxylic acid, which was obtainedby following a procedure analogous to that outlined in steps 1 & 3 ofexample 162. LCMS: m/z 370.1 (M+H)⁺.

Example 3991′-{[1-(4-Methylphenyl)cyclopropyl]carbonyl}-7H-spiro[furo[3,4-b]pyridine-5,3′-pyrrolidin]-7-one

This compound was prepared by using a procedure analogous to thatoutlined in example 90. LCMS: m/z 349.1 (M+H)⁺.

Example 4001′-({1-[4-(Trifluoromethyl)phenyl]cyclopropyl}carbonyl)-7H-spiro[furo[3,4-b]pyridine-5,3′-pyrrolidin]-7-one

This compound was prepared by using a procedure analogous to thatoutlined in example 298. LCMS: m/z 403.1 (M+H)⁺.

Example 4011′-{[1-(4-Methoxyphenyl)cyclopropyl]carbonyl}-7H-spiro[furo[3,4-b]pyridine-5,3′-pyrrolidin]-7-one

This compound was prepared by using a procedure analogous to thatoutlined in example 298. LCMS: m/z 365.1 (M+H)⁺.

Example 4021′-({1-[4-(Trifluoromethoxy)phenyl]cyclopropyl}carbonyl)-7H-spiro[furo[3,4-b]pyridine-5,3′-pyrrolidin]-7-one

This compound was prepared by using a procedure analogous to thatoutlined in example 298. LCMS: m/z 419.0 (M+H)⁺.

Example 4031′-{[1-(4-Fluorophenyl)cyclopropyl]carbonyl}-7H-spiro[furo[3,4-b]pyridine-5,3′-pyrrolidin]-7-one

This compound was prepared by using a procedure analogous to thatoutlined in example 298. LCMS: m/z 353.1 (M+H)⁺.

Example 4041′-{[1-(2-Chloro-4-fluorophenyl)cyclopropyl]carbonyl}-7H-spiro[furo[3,4-b]pyridine-5,3′-pyrrolidin]-7-one

This compound was prepared by using a procedure analogous to thatoutlined in example 298. LCMS: m/z 387.0 (M+H)⁺.

Example 4051′-{[1-(2,4-Difluorophenyl)cyclopropyl]carbonyl}-7H-spiro[furo[3,4-b]pyridine-5,3′-pyrrolidin]-7-one

This compound was prepared by using a procedure analogous to thatoutlined in example 298. LCMS: m/z 371.0 (M+H)⁺.

Example 4061′-{[1-(3-Chlorophenyl)cyclopropyl]carbonyl}-7H-spiro[furo[3,4-b]pyridine-5,3′-pyrrolidin]-7-one

This compound was prepared by using a procedure analogous to thatoutlined in example 298. LCMS: m/z 369.0 (M+H)⁺.

Example 4071′-{[(1-(3,4-Dichlorophenyl)cyclopropyl]carbonyl}-7H-spiro[furo[3,4-b]pyridine-5,3′-pyrrolidin]-7-one

This compound was prepared by using a procedure analogous to thatoutlined in example 298. LCMS: m/z 403.0 & 405.0 (M+H)⁺.

Example 4081′-{[1-(2,3-Difluorophenyl)cyclopropyl]carbonyl}-7H-spiro[furo[3,4-b]pyridine-5,3′-pyrrolidin]-7-one

This compound was prepared by using a procedure analogous to thatoutlined in example 298. LCMS: m/z 371.0 (M+H)⁺.

Example 4091′-{[1-(2,4-Dichlorophenyl)cyclopropyl]carbonyl}-7H-spiro[furopyridine-5,3′-pyrrolidin]-7-one

This compound was prepared by using a procedure analogous to thatoutlined in example 90. LCMS: m/z 403.0 & 405.0 (M+H)⁺.

Example 410 Ethyl4-[5-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)pyridin-2-yl]piperazine-1-carboxylate

tert-Butyl4-[5-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)pyridin-2-yl]piperazine-1-carboxylate(10.4 mg, 0.0000200 mol, prepared by a procedure similar to that insteps 1-3 of example 163) was treated with hydrogen chloride in1,4-dioxane (4.0 M, 20.0 μL) at rt for 1 h. The solvent was evaporatedand acetonitrile (1.00 mL, 0.0191 mol) was added to the residue followedby N,N-diisopropylethylamine (20.0 μL, 0.000115 mol) and ethylchloroformate (5.0 g, 0.000052 mol). The mixture was stirred at rt for30 min, and adjusted to be acidic (pH=2.0) with TFA, and diluted withmethanol (0.8 mL). The desired product from the resulting solution wasisolated and purified by prep-HPLC. LCMS: m/z 491.2 (M+H)⁺.

Example 411(1R)-1′-[(1-{6-[4-(ethylsulfonyl)piperazin-1-yl]pyridin-3-yl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in example 164. LCMS: m/z 511.2 (M+H)⁺.

Example 412(1R)-1′-({1-[6-(4-Methylpiperazin-1-yl)pyridin-3-yl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in steps 1-4 of example 163, with the exception that in step 4the free amine compound underwent a reductive alkylation outlined belowinstead of being reacted with a carbamoyl chloride, as outlined below.

N,N-Diisopropylethylamine (8.3 μL, 0.000048 mol) was added to(1R)-1′-{[1-(6-piperazin-1-ylpyridin-3-yl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one(10.0 mg, 0.0000239 mol) and formaldehyde (8.90 μL, 0.000119 mol) intetrahydrofuran (0.5 mL, 0.006 mol) and acetonitrile (0.5 mL, 0.01 mol).To this solution was added sodium triacetoxyborohydride (25 mg, 0.00012mol) and the reaction was stirred at room temperature overnight. LCMS:m/z 433.2 (M+H)⁺.

Example 413(1R)-1′-({1-[6-(4-Phenylpiperazin-1-yl)pyridin-3-yl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in steps 1-3 of example 163. LCMS: m/z 495.1 (M+H)⁺.

Example 414(1R)-1′-[(1-{6-[4-(3-Methylbutanoyl)piperazin-1-yl]pyridin-3-yl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in steps 1-4 of example 163, with the exception that in step 4the amide was formed by BOP mediated coupling as outlined below.

4-Methylmorpholine (2.0×10⁻¹ μL, 0.00018 mol) was added to a mixture of(1R)-1′-{[1-(6-piperazin-1-ylpyridin-3-yl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one(15 mg, 0.000036 mol), butanoic acid, 3-methyl-(4.4 mg, 0.000043 mol)and benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (19 mg, 0.000043 mol) in acetonitrile (0.7 mL, 0.01mol). The reaction mixture was stirred at room temperature overnight.The crude product was purified by prep-LCMS. LCMS: m/z 503.3 (M+H)⁺.

Example 415(1R)-1′-[(1-{6-[4-(Cyclopropylmethyl)piperazin-1-yl]pyridin-3-yl]cyclopropyl)carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in steps 1-4 of example 163, with the exception that in step 4the free amine was alkylated by a reductive alkylation outlined below.

N,N-Diisopropylethylamine (8.3 μL, 0.000048 mol) was added to(1R)-1′-{([1-(6-piperazin-1-ylpyridin-3-yl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one(10.0 mg, 0.0000239 mol) and cyclopropanecarboxaldehyde (8.93 μL,0.000119 mol) in tetrahydrofuran (0.5 mL, 0.006 mol) and acetonitrile(0.5 mL, 0.01 mol) followed by sodium triacetoxyborohydride (25 mg,0.00012 mol). The reaction mixture was stirred at room temperatureovernight. LCMS: 473.2 (M+H)⁺.

Example 416(1R)-1′-({1-[6-(2,5-Dihydro-1H-pyrrol-1-yl)pyridin-3-yl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in steps 1-3 of example 163. LCMS: m/z 402.2 (M+H)⁺.

Example 417(1R)-1′-{[1-(6-Piperidin-1-ylpyridin-3-yl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in steps 1-3 of example 163. LCMS: m/z 418.1 (M+H)⁺.

Example 418(1R)-1′-({1-[4-(4-Methyl-2-oxopiperazin-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in steps 1-2 of example 259, followed by a reductive aminationof the resulting free amine by using a procedure that was analogous tothat used in example 415. LCMS: m/z 446.1 (M+H)⁺.

Example 419(1R)-1′-({1-[4-(4-Acetyl-2-oxopiperazin-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in example 259, steps 1-3.

Example 420 tert-Butyl4-[4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]piperazine-1-carboxylate

A mixture of(1R)-1′-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one(0.50 g, 0.0014 mol, see steps 1 & 2 of example 96), tert-butylpiperazine-1-carboxylate (0.30 g, 0.0016 mol), sodium tert-butoxide(0.31 g, 0.0033 mol), palladium acetate (9 mg, 0.00004 mol) and2-(di-t-butylphosphino)biphenyl (10 mg, 0.00004 mol) was degassed andthen charged with nitrogen. To the mixture was added 1,4-dioxane (10.0mL, 0.128 mol) and the resulting mixture was refluxed for 1 h.

Example 421(1R)-1′-({1-[4-(4-Isobutyrylpiperazin-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-oneStep 1.(1R)-1′-({1-(4-piperazin-1-ylphenyl)cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

tert-Butyl4-[4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]piperazine-1-carboxylate(0.65 g, 0.0012 mol, see example 420) was dissolved in methylenechloride (2.0 mL, 0.031 mol) and to this solution was added hydrogenchloride in 1,4-dioxane (4.0 M, 5.0 mL) and the reaction mixture wasstirred at rt for 2 h. The mixture was diluted with ether andprecipitate formed was filtered and dried to give the desired product.LC-MS: 418.2 (M+H)⁺

Step 2

Propanoyl chloride (5.0 μL, 0.000057 mol) was added to a solution of(1R)-1′-{[1-(4-piperazin-1-ylphenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one(20.0 mg, 0.0000478 mol) and N,N-diisopropylethylamine (27 μL, 0.00016mol) in methylene chloride (1.0 mL, 0.016 mol) and the mixture wasstirred for 1 h. The solvent was removed and the crude product waspurified by prep-HPLC. LC-MS: 488.2 (M+H)⁺

Example 422(1R)-1′-[(1-{4-[4-(Cyclopropylcarbonyl)piperazin-1-yl]phenyl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in steps 1 & 2 of example 421. LCMS: m/z 486.2 (M+H)⁺.

Example 423(1R)-1′-[(1-{4-[4-(Methylsulfonyl)piperazin-1-yl]phenyl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in steps 1 & 2 of example 421.

Example 424(1R)-1′-({1-[4-(4-Methylpiperazin-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

Formaldehyde (10.0 mg, 0.000333 mol) was added to a solution of(1R)-1′-{[1-(4-piperazin-1-ylphenyl)cyclopropyl}carbonyl]-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one(0.13 g, 0.00032 mol, example 421, step 1) in methanol (1.0 mL, 0.025mol) followed by sodium triacetoxyborohydride (0.20 g, 0.00095 mol), andthe mixture was stirred for 1 h. The crude product was purified byprep-HPLC. LC-MS: 432.3 (M+H)+

Example 425N-Methyl-N-[4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]cyclopropanecarboxamide

This compound was prepared by using a procedure analogous to acombination of step 1 of example 102 and steps 3-4 of example 258. LCMS:m/z 431.1 (M+H)⁺.

Example 426N-[4-(1-{[(1R)-3-Oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]acetamide

This compound was prepared by using a procedure analogous to thatoutlined in steps 1-4 of example 261. LCMS: m/z 391.2 (M+H)⁺.

Example 427(1R)-1′-({1-[4-(2-Oxopyrrolidin-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in example 257. LCMS: m/z 417.2 (M+H)⁺.

Example 428(1R)-1′-({1-[4-(2-Oxo-1,3-oxazolidin-3-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 257. LCMS: m/z 419.2 (M+H)⁺.

Example 429(1R)-1′-({1-[4-(1H-Pyrazol-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 102. LCMS: m/z 400.1 (M+H)⁺.

Example 430(1R)-1′-({1-[4-(2-Oxopiperidin-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 257. LCMS: m/z 431.2 (M+H)⁺.

Example 4311-Methyl-3-[4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]imidazolidine-2,4-dione

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 257. LCMS: m/z 446.2 (M+H)⁺.

Example 432(1R)-1′-{[1-(4-Morpholin-4-ylphenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

A mixture of(1R)-1′-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one(30.0 mg, 0.0000816 mol, example 83), morpholine (8.5 μL, 0.000098 mol),sodium tert-butoxide (19 mg, 0.00020 mol), palladium acetate (0.5 mg,0.000002 mol) and 2-(di-t-butylphosphino)biphenyl (0.7 mg, 0.000002 mol)was degassed and charged with nitrogen. To the mixture was added1,4-dioxane (1.0 mL, 0.013 mol). The resulting mixture was refluxedovernight. The crude product was purified prep-HPLC. LC-MS: 419.2 (M+H)+

Example 4331-[4-(1-{[3-Phenylpyrrolidin-1-yl]carbonyl}cyclopropyl)phenyl]pyrrolidine-2-one

This compound was prepared by using a procedure analogous to thatoutlined in step 1 of example 102, starting with(3R)-1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}-3-phenylpyrrolidine(example 29). LCMS: m/z 375.2 (M+H)⁺.

Example 4343-[4-(1-{[3-Phenylpyrrolidin-1-yl]carbonyl}cyclopropyl)phenyl]-1,3-oxazolidin-2-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 102, step 1, starting with(3R)-1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}-3-phenylpyrrolidine(example 29). LCMS: m/z 377.2 (M+H)⁺.

Example 435 Methyl4-(4-{1-[(3-phenylpyrrolidin-1-yl)carbonyl]cyclopropyl}phenyl)piperazine-1-carboxylate

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 258. LCMS: m/z 434.2 (M+H)⁺.

Example 436 Ethyl4-(4-{1-[(3-phenylpyrrolidin-1-yl)carbonyl]cyclopropyl}phenyl)piperazine-1-carboxylate

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 258.

Example 4371-Isobutyryl-4-(4-{1-[(3-phenylpyrrolidin-1-yl)carbonyl]cyclopropyl}phenyl)piperazine

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 258. LCMS: m/z 446.3 (M+H)⁺.

Example 4381-Acetyl-4-(4-{1-[(3-phenylpyrrolidin-1-yl)carbonyl]cyclopropyl}phenyl)piperazine

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 258. LCMS: m/z 418.3 (M+H)⁺.

Example 4391-(Cyclopropylcarbonyl)-4-(4-{1-[(3-phenylpyrrolidin-1-yl)carbonyl]cyclopropyl}phenyl)piperazine

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 258. LCMS: m/z 444.3 (M+H)⁺.

Example 4401-Isobutyryl-4-(5-{1-[(3-phenylpyrrolidin-1-yl)carbonyl]cyclopropyl}pyridin-2-yl)piperazine

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 163. LCMS: m/z 447.3 (M+H)⁺.

Example 4411-(Cyclopropylcarbonyl)-4-(5-{1-[(3-phenylpyrrolidin-1-yl)carbonyl]cyclopropyl}pyridin-2-yl)piperazine

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 163. LCMS: m/z 445.3 (M+H)⁺.

Example 442(1R)-1′-[(1-Pyridin-3-ylcyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in steps 1-2 and 4 of example 96. LCMS: m/z 335.1 (M+H)⁺.

Example 443N-Methyl-4-[5-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)pyridin-2-yl]benzamideStep 1.4-[5-(1-{[(1R)-3-oxo-1H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)pyridin-2-yl]benzoicacid

This compound was prepared by using a procedure analogous to thatoutlined in steps 1-2 of example 173. LCMS: m/z 455.2 (M+H)⁺.

Step 2

4-Methylmorpholine (12 μL, 0.00011 mol) was added to a mixture of4-[5-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)pyridin-2-yl]benzoicacid (13 mg, 0.000029 mol), methylammonium chloride (2.9 mg, 0.000043mol), and benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (14 mg, 0.000031 mol) in N,N-dimethylformamide (0.5mL, 0.006 mol), and the resulting mixture was stirred at rt for 2 h. Thecrude product was purified by prep-LCMS. LCMS: m/z 468.2 (M+H)⁺.

Example 444N,N-Dimethyl-4-[5-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)pyridin-2-yl]benzamide

This compound was prepared by using a procedure analogous to thatoutlined in steps 1-2 of example 443. LCMS: m/z 482.2 (M+H)⁺.

Example 445(1R)-1′-[(1-{6-[4-(Methylsulfonyl)phenyl]pyridin-3-yl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in steps 1-2 of example 173. LCMS: m/z 489.1 (M+H)⁺.

Example 446(1R)-1′-{[1-(4-Methoxyphenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in steps 1-2 and 4 of example 96. LCMS: m/z 364.2 (M+H)⁺.

Example 447(1R)-1′-({1-[4-(Pyridin-2-yloxy)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in steps 1-2 of example 114. LCMS: m/z 427.1 (M+H)⁺449.1(M+Na)⁺.

Example 448(1R)-1′-({1-[4-(Pyridin-3-ylmethoxy)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in steps 1-2 of example 114. LCMS: m/z 441.1 (M+H)⁺ 463.1(M+Na)⁺.

Example 449(1R)-1′-({1-[4-(Isoquinolin-1-ylmethoxy)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in steps 1-2 of example 114. LCMS: m/z 491.2 (M+H)⁺.

Example 4501′-{[1-(4-Vinylphenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in example 119. LCMS: m/z 360.1 (M+Hr 382.0 (M+Na)⁺.

Example 451 Methyl4-[4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]-3,6-dihydropyridine-1(2H)-carboxylateStep 1.1-{4-[1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}cyclopropanecarboxylic acid

A mixture of1-{4-[1-(tert-butoxycarbonyl)-4-hydroxypiperidin-4-yl]phenyl}cyclopropanecarboxylicacid (300 mg, prepared as described in example 210, steps 1 & 2) andtrifluoroacetic acid 2 mL was stirred at rt for 5 h. The reactionmixture was then concentrated. The crude product was dissolved intetrahydrofuran (4 mL, 0.05 mol) and to this was addeddi-tert-butyldicarbonate (333 mg, 0.00152 mol) andN,N-diisopropylethylamine (6.0×10⁻² μL, 0.0035 mol). The mixture wasstirred at rt for 5 h and then diluted with AcOEt, washed with saturatedNaHCO₃ aqueous solution and 1M HCl successively, dried with MgSO₄, andconcentrated in-vacuo to afford the desired product.

Step 2. Methyl4-[4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate

The title compound was prepared using a procedure analogous to that insteps 3-4 of example 163, with the omission of theLiOH-promoted-hydrolysis. LCMS: m/z 473.3 (M+H)⁺.

Example 452 Ethyl4-[4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate

This compound was prepared by using a procedure analogous to thatoutlined in steps 1-2 of example 451. LCMS: m/z 487.3 (M+H)⁺.

Example 453(1R)-1′-({1-[4-(1-Acetyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in steps 1 & 2 of example 451. LCMS: m/z 457.3 (M+H)⁺.

Example 454(1R)-1′-[(1-{4-[1-(3-Methylbutanoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in steps 1 & 2 of example 451, with the exception that for thelast step the acid chloride was replaced by the corresponding carboxylicacid as described below: A mixture of 3-methyl butanoic acid (16 mg,0.00015 mol), benzotriazol-1-yloxytris(dimethylamino) phosphoniumhexafluorophosphate (38 mg, 0.000085 mol), and N,N-diisopropylethylamine(4.0×10⁻¹ μL, 0.00023 mol) dissolved in N,N-dimethylformamide (0.5 mL,0.006 mol) was stirred at rt for 2 h. The reaction mixture was thendiluted with MeOH and the crude product was purified by prep-HPLC toafford the desired product. LCMS: m/z 499.3 (M+H)⁺.

Example 4555-Hydroxy-1′-{[1-(4-methylphenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

To a solution of5-methoxy-1′-{[1-(4-methylphenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one(40 mg, 0.0001 mol) in tetrahydrofuran (2 mL, 0.02 mol) was addedL-Selectride® in tetrahydrofuran (1.0 M, 0.53 mL) and the resultingsolution was heated to 120° C. for 50 minutes using microwaveirradiation. To the reaction mixture was added a few drops of water toquench the reaction. Then the reaction mixture was concentrated andabout. 3 mL of concentrated HCl aqueous solution was added to dissolvethe residue. The resulting solution was stirred at rt for 2 h. The crudeproduct was purified using prep-HPLC. LCMS: m/z 364.2 (M+H)⁺.

Example 455a1′-{[1-(4-Methylphenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-5-ol

This compound was prepared by using a procedure analogous to thatoutlined in example 454. LCMS: m/z 350.2 (M+H)⁺.

Example 456(1R)-1′-({1-[4-(Pyrrolidin-1-ylmethyl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-oneStep 1. 1-[4-(pyrrolidin-1-ylmethyl)phenyl]cyclopropanecarbonitrile

A mixture of 1-(4-formylphenyl)cyclopropanecarbonitrile (0.30 g, 0.0018mol), pyrrolidine (0.18 mL, 0.0021 mol) and sodium triacetoxyborohydride(0.74 g, 0.0035 mol) in methanol (5.0 mL, 0.12 mol) was stirred at rtfor 1 h. The reaction mixture was adjusted to be basic (pH=12) andextracted with ethyl acetate. The combined organic extract was washedwith brine, dried and concentrated to provide the desired product.LC-MS: 227.1 (M+H)⁺

Step 2

The title compound was prepared by using a procedure analogous to thatoutlined in steps 1, 2 and 4 of example 96.

Example 457(1R)-1′-{[1-(6-Pyrrolidin-1-ylpyridin-3-yl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in steps 1-3 of example 163. LCMS: m/z 405.1 (M+H)⁺.

Example 458(1R)-1′-({1-[6-(4-Phenylpiperazin-1-yl)pyridin-3-yl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in steps 1-3 of example 163. LCMS: m/z 496.2 (M+H)⁺.

Example 459 Methyl4-[5-(1-{[(1R)-3-oxo-1′H,3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)pyridin-2-yl]piperazine-1-carboxylate

This compound was prepared by using a procedure analogous to thatoutlined in steps 1-4 of example 163. LCMS: m/z 478.2 (M+H)⁺.

Example 460 Ethyl4-(5-{1-[(3-oxo-1′H,3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-1′-yl)carbonyl]cyclopropyl}pyridin-2-yl)piperazine-1-carboxylate

This compound was prepared by using a procedure analogous to thatoutlined in steps 1-4 of example 163.

Example 461 Isopropyl4-(5-{1-[(3-oxo-1′H,3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-1′-yl)carbonyl]cyclopropyl}pyridin-2-yl)piperazine-1-carboxylate

This compound was prepared by using a procedure analogous to thatoutlined in steps 1-4 of example 163. LCMS: m/z 506.2 (M+H)⁺.

Example 4621′-({1-[6-(4-Chlorophenyl)pyridin-3-yl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in steps 1-2 of example 173. LCMS: m/z 446.1 & 448.1 (M+H)⁺.

Example 4631′-({1-[6-(4-Fluorophenyl)pyridin-3-yl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in steps 1-2 of example 173. LCMS: m/z 430.2 (M+H)⁺.

Example 4641′-({1-[6-(4-Fluoro-2-methylphenyl)pyridin-3-yl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in steps 1-2 of example 173. LCMS: m/z 444.2 (M+H)*.

Example 4651′-[(1-Quinolin-4-ylcyclopropyl)carbonyl]-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in steps A & B of example 95. LCMS: m/z 386.1 (M+H)⁺.

Example 4664-Chloro-1′-[(1-quinolin-4-ylcyclopropyl)carbonyl]-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in steps 1-3 of example 227. LCMS: m/z 420.0 & 422.0 (M+H)⁺.

Example 4674-Hydroxy-1′-[(1-quinolin-4-ylcyclopropyl)carbonyl]-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in steps 1-3 of example 227. LCMS: m/z 402.1 (M+H)⁺.

Example 4684-Methoxy-1′-[(1-quinolin-4-ylcyclopropyl)carbonyl]-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in steps 1-3 of example 227. LCMS: m/z 416.1 (M+H)⁺.

Example 4691′-[(1-{4-[(4-Fluorobenzyl)oxy]phenyl}cyclopropyl)carbonyl]-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in steps 1 & 2 of example 104. LCMS: m/z 459.2 (M+H)⁺.

Example 4701′-{[1-(4-{[4-(Trifluoromethyl)benzyl]oxy}phenyl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in steps 1 & 2 of example 104. LCMS: m/z 509.2 (M+H)⁺.

Example 4711′-[(1-{4-[(2-Chloro-4-fluorobenzyl)oxy]phenyl}cyclopropyl)carbonyl]-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in steps 1 & 2 of example 104.

Example 4721′-[(1-{4-[(4-Bromo-2-fluorobenzyl)oxy]phenyl}cyclopropyl)carbonyl]-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in steps 1 & 2 of example 104. LCMS: m/z 537.1 (M+H)⁺559.1

Example 4733-Fluoro-4-[(4-{1-[(3-oxo-1′H,3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-1′-yl)carbonyl]cyclopropyl}phenoxy)methyl]benzonitrile

A mixture of1′-[(1-{4-[(4-bromo-2-fluorobenzyl)oxy]phenyl}cyclopropyl)carbonyl]-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one(18 mg, 0.000033 mol, example 474), zinc cyanide (3.9 mg, 0.000033 mol),tetrakis(triphenylphosphine)palladium(0) (2 mg, 0.000002 mol), andtetra-N-butylammonium bromide (2.7 mg, 0.0000084 mol) inN,N-dimethylformamide (0.5 mL, 0.006 mol) was microwave irradiated at170° C. for 5 min. After cooling, the crude product was purified withprep-hplc to afford 12.4 mg of pure product. LCMS: m/z 484.2 (M+H)⁺.

Example 4741′-[(1-{4-[1-(2-Fluorophenyl)ethoxy]phenyl}cyclopropyl)carbonyl]-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis in example 105. LCMS: m/z 473.2 (M+H)⁺.

Example 4754-[1-(4-{1-[(3-Oxo-1′H,31′-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-1′-yl)carbonyl]cyclopropyl}phenoxy)ethyl]benzonitrile

This compound was prepared by using a procedure analogous to thatoutlined in example 473, using the title compound of example 300 as thebenzyl bromide starting material. LCMS: m/z 480.2 (M+H)⁺.

Example 4761′-({1-[4-(Quinolin-2-ylmethoxy)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in steps 1-2 of example 104. LCMS: m/z 492.2 (M+H)⁺

Example 4771′-{[1-(4-Methoxyphenyl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in step B of example 95. LCMS: m/z 365.1 (M+H)⁺

Example 4786-Chloro-1′-{[1-(4-methoxyphenyl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis in example 232. LCMS: m/z 399.4 (M+H)⁺

Example 4791′-{[1-(4-Methoxyphenyl)cyclopropyl]carbonyl}-6-(trifluoromethyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis in example 222. LCMS: m/z 433.1 (M+H)'

Example 4801′-({1-[4-(Cyclopentyloxy)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in steps 1-3 of example 213. LCMS: m/z 419.2 (M+H)⁺ 441.1(M+Na)⁺.

Example 4811′-({1-[4-(Allyloxy)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis in example 215. LCMS: m/z 391.3 (M+H)⁺ 413.2(M+Na)⁺.

Example 4821′-({1-[4-(2-Methoxyethoxy)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in steps 1-3 of example 213. LCMS: m/z 409.2 (M+H)⁺ 431.2(M+Na)⁺.

Example 4831′-({1-[4-(Cyclopropylmethoxy)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis in example 215. LCMS: m/z 405.1 (M+H)⁺ 427.1(M+Na)⁺.

Example 4841′-{[1-(4-Methylphenyl)cyclopropyl]carbonyl}-6-(trifluoromethyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis in example 222. LCMS: m/z 417.1 (M+H)⁺

Example 4851′-{[1-(4-Methylphenyl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in step B of example 95.

Example 4861′-({1-[4-(Trifluoromethyl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in steps A & B of example 95. LCMS: m/z 403.1 (M+H)⁺

Example 4871′-{[1-(4-Vinylphenyl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis in example 123. LCMS: m/z 361.0 (M+H)⁺ 383.1(M+Na)⁺.

Example 4881′-[(1-{4-[(E)-2-Pyridin-2-ylvinyl]phenyl}cyclopropyl)carbonyl]-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis in example 122. LCMS: m/z 438.2 (M+H)⁺ 460.1(M+Na)⁺.

Example 4891′-({1-[4-(1-Isobutyryl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in steps 1-5 of example 210. LCMS: m/z 486.2 (M+H)⁺.

Example 4901′-({1-[4-(1-Acetylpiperidin-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in steps 1 and 2 of example 451 with the exception that step 1was modified by an addition of 20 equivalent of triethylsilane duringthe dehydration by treatment with TFA. LCMS: m/z 460.2 (M+H)⁺.

Example 491 Ethyl4-(4-{1-[(3-oxo-1′H,3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-1′-yl)carbonyl]cyclopropyl}phenyl)piperidine-1-carboxylate

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis in example 490. LCMS: m/z 490.2 (M+Hr.

Example 4921′-({1-[4-(1-Isobutyrylpiperidin-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis in example 454, with the exception that step1 of example 451 was modified by an addition of 20 equivalent oftriethylsilane during the dehydration with TFA.

Example 4931′-({1-[4-(1-Propionylpiperidin-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis in example 492. LCMS: m/z 474.2 (M+H)⁺.

Example 4941′-[(1-{4-[1-(3-Methylbutanoyl)piperidin-4-yl]phenyl}cyclopropyl)carbonyl]-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis in example 492. LCMS: m/z 502.3 (M+H)⁺.

Example 4951′-({1-[4-(2-Isopropyl-1,3-thiazol-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis in example 142. LCMS: m/z 460.2 (M+H)⁺.

Example 4961′-[(1-{4-[2-(Dimethylamino)-1,3-thiazol-4-yl]phenyl}cyclopropyl)carbonyl]-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis in example 142. LCMS: m/z 461.2 (M+H)⁺.

Example 4971′-({1-[4-(2-Amino-1,3-thiazol-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis in example 142. LCMS: m/z 433.2 (M+H)⁺.

Example 4983-Fluoro-4-{1-[(3-oxo-1′H,3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-1′-yl)carbonyl]cyclopropyl}benzonitrile

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis in example 208. LCMS: m/z 378.1 (M+H)⁺.

Example 4991′-({1-[2-Fluoro-4-(4-methyl-1,3-thiazol-2-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

Into a microwave vial was added3-fluoro-4-{1-[(3-oxo-1′H,3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-1′-yl)carbonyl]cyclopropyl}benzenecarbothioamide(35 mg, 0.000085 mol, prepared by subjecting the title compound inexample 498 to analogous reaction conditions outlined in example 209) inethanol (0.300 mL, 0.00514 mol) and N,N-dimethylformamide (0.75 mL,0.0097 mol). To this solution was added chloroacetone (0.2 mL, 0.002mol) and the tube was sealed and heated at 80° C. for 4 h using an oilbath. After ˜3 h the mixture became homogeneous. LCMS indicated that thereaction was complete. The crude product was purified by prep-LCMS.LCMS: m/z 450.2 (M+H)⁺.

Example 500(1R)-1′-[(1-{-4-[5-(Trifluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl}cyclopropyl)carbonyl]-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in example 338. LCMS: m/z 471.1 (M+H)⁺.

Example 5011′-({1-[4-(3-Methylisoxazol-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-oneStep 1. 1-(4-ethynylphenyl)cyclopropanecarbonitrile

A mixture of (4-ethynylphenyl)acetonitrile (1.0 g, 0.0071 mol),1-bromo-2-chloro-ethane (1200 μL, 0.014 mol), benzyltriethylammoniumchloride (0.1 g, 0.0004 mol) and 1 ml of 50% NaOH water (w/v) was heatedat 50° C. for 4 hours. The product was extracted with EtOAc and thecombined organic phases were washed with water and brine successively,dried over Na₂SO₄, filtered, and concentrated in-vacuo to afford 1.1 gof the desired product, which was used in the following step withoutfurther purification.

Step 2. 1-[4-(3-methylisoxazol-4-yl)phenyl]cyclopropanecarbonitrile

To a mixture of 1-(4-ethynylphenyl)cyclopropanecarbonitrile (200 mg,0.001 mol) acetaldoxime (71 mg, 0.0012 mol) in tetrahydrofuran (5.0 mL,0.062 mol) was added N-chlorosuccinimide (160 mg, 0.0012 mol) inportions with stirring. After the addition was complete, triethylamine(170 μL, 0.0012 mol) was added. The mixture was stirred at rt for 2days. The reaction mixture was diluted with ethyl acetate and washedwith water and brine successively, dried over MgSO₄ and filtered. Thefiltrate was concentrated to afford the desired product in quantitativeyield.

Step 3

The title compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 212, steps 3 & 4. LCMS: m/z 416.1(M+H)⁺.

Example 502(1R)-1′-({1-[4-(2-Pyridin-2-ylethyl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

A mixture of(1R)-1′-[(1-{4-[(E)-2-pyridin-2-ylvinyl]phenyl}cyclopropyl)carbonyl]-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one(20 mg, 0.00004 mol, example 488), 10% Pd—C in methanol (1 mL, 0.02 mol)was stirred under a hydrogen atmosphere (balloon) for 1.5 h. Thereaction mixture was then filtered and concentrated to afford thedesired product. LCMS: m/z 440.2 (M+H)⁺; 462.2 (M+Na)⁺.

Example 5031′-({1-[2-Fluoro-4-(1H-pyrazol-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in example 126.

Example 5041′-({1-[2-Fluoro-4-(3-methyl-1H-pyrazol-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in example 126.

Example 5051′-({1-[4-(3-Amino-1H-pyrazol-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in example 126. LCMS: m/z 416.1 (M+H)⁺.

Example 5061′-({1-[4-(1H-Benzimidazol-1-yl)-2-fluorophenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in example 130.

Example 5071′-[(1-{2-Fluoro-4-[2-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}cyclopropyl)carbonyl]-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in example 130.

Example 5081′-({1-[4-(2-Methoxy-1H-benzimidazol-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in example 207. LCMS: m/z 481.2 (M+H)⁺.

Example 509 Ethyl4-(4-{1-[(3-oxo-1′H,3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-1′-yl)carbonyl]cyclopropyl}phenyl)piperazine-1-carboxylate

This compound was prepared by using a procedure analogous to thatoutlined in steps 1-4 of example 163, with the exception that step 2 wasreplaced by the following protocol: A mixture of methyl1-(4-bromophenyl)cyclopropanecarboxylate (0.53 g, 0.0021 mol),tert-butyl piperazine-1-carboxylate (0.42 g, 0.0023 mol), potassiumphosphate (0.66 g, 0.0031 mol), tris(dibenzylideneacetone)dipalladium(0)(57.0 mg, 0.0000622 mol) and o-(dicyclohexylphosphino)biphenyl (21.8 mg,0.0000622 mol) was degassed and then charged with nitrogen. To themixture was added toluene (8.0 mL, 0.075 mol) and the resulting mixturewas heated at 100° C. overnight. The mixture was filtered through ashort silica gel pad and the solvent was removed under reduced pressure.The crude product was purified by CombiFlash eluting with hexane/EtOAc(max. EtOAc 20%). LC-MS: 361.2 (M+H)⁺, 305.2 (M+H-56)+

Example 510 Isopropyl4-[4-(1-{[(1R)-3-oxo-1′H,3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-yl]carbonyl}cyclopropyl)phenyl]piperazine-1-carboxylate

This compound was prepared by using a procedure analogous to thatoutlined in example 509. LCMS: m/z 505.2 (M+H)⁺.

Example 511(1R)-1′-({1-[4-(4-Propionylpiperazin-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in example 509. LCMS: m/z 475.2 (M+H)⁺.

Example 512(1R)-1′-({1-[4-(4-Isobutyrylpiperazin-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in example 509. LCMS: m/z 489.2 (M+H)⁺.

Example 513(1R)-1′-[(1-{4-[4-(Cyclopropylcarbonyl)piperazin-1-yl]phenyl}cyclopropyl)carbonyl]-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 509. LCMS: m/z 487.3 (M+H)⁺.

Example 5141′-[(1-{4-[4-(Methylsulfonyl)piperazin-1-yl]phenyl}cyclopropyl)carbonyl]-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 509. LCMS: m/z 497.2 (M+H)⁺.

Example 5151′-({1-[4-(2-Oxopyridin-1(2H)-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 257. LCMS: m/z 428.2 (M+H)⁺.

Example 516Methyl[4-(1-{[(1R)-3-oxo-1′H,3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]carbamate

This compound was prepared by using a procedure analogous to acombination of steps 1-3 of example 261 and step 2 of example 263. LCMS:m/z 408.1 (M+H)⁺.

Example 517N-[4-(1-{[(1R)-3-Oxo-1′H,3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]methanesulfonamide

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 262. LCMS: m/z 428.1 (M+H)⁺.

Example 518(1R)-1′-{[1-(2-Fluorophenyl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 95. LCMS: m/z 353.1 (M+H)⁺.

Example 5191′-{[1-(2-Chlorophenyl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 95. LCMS: m/z 369.5 (M+H)⁺.

Example 5201′-{[1-(2-Bromophenyl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 95. LCMS: m/z 414.1 (M+H)⁺.

Example 5211′-({1-[2-(Trifluoromethyl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 95. LCMS: m/z 403.1 (M+H)⁺.

Example 5221′-{[1-(2-Methoxyphenyl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 95. LCMS: m/z 365.1 (M+H)⁺.

Example 5231′-{[1-(2-Methylphenyl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 95. LCMS: m/z 349.1 (M+H)⁺.

Example 524(1R)-1′-{[1-(2,3-Difluorophenyl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 95. LCMS: m/z 371.1 (M+H)⁺.

Example 5251′-{[1-(2-Chloro-6-fluorophenyl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 95. LCMS: m/z 387.4 (M+H)⁺.

Example 5261′-{[1-(1-Naphthyl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 95. LCMS: m/z 385.1 (M+H)⁺.

Example 5271′-{[1-(2-Fluorophenyl)cyclopropyl]carbonyl}-6-(trifluoromethyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 222. LCMS: m/z 421.1 (M+H)⁺.

Example 5286-Chloro-1′-{[1-(4-methylphenyl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 232. LCMS: m/z 383.5 (M+H)⁺.

Example 5296-Chloro-1′-({1-[4-(trifluoromethyl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 232. LCMS: m/z 436.3 (M+H)⁺.

Example 5306-Chloro-1′-{[1-(2,4-difluorophenyl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 232. LCMS: m/z 404.3 (M+H)⁺.

Example 5316-Chloro-1′-({1-[3-(difluoromethoxy)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 95. LCMS: m/z 435.4 (M+H)⁺.

Example 5321′-{[1-(2,4-Dichlorophenyl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-oneStep 1. 1-{[1-(2,4-dichlorophenyl)cyclopropyl]carbonyl}pyrrolidin-3-ol

To a solution of 3-pyrrolidinol (0.861 mL, 0.0106 mol) inN,N-dimethylformamide (5 mL, 0.06 mol) were added1-(2,4-dichlorophenyl)cyclopropanecarboxylic acid and BOP. After themixture was stirred for 3 min, DIEA was added. After the reactionmixture was stirred for 3 h, the solution was diluted with AcOEt, washedwith sat'd. NaHCO₃ aq. (×3), water and brine successively, dried withMgSO₄, and concentrated in-vacuo.

Step 2. 1-{[1-(2,4-dichlorophenyl)cyclopropyl]carbonyl}pyrrolidin-3-one

To a solution of1-{[1-(2,4-dichlorophenyl)cyclopropyl]carbonyl}pyrrolidin-3-ol (3.05 g,0.0102 mol) in acetone (50 mL, 0.7 mol) was added Jones oxidant in water(8.00 M, 2.54 mL) at 0 degrees celsius and the resulting solution wasstirred at rt for 1 hour. The mixture was filtered through celite andthe filtrate was concentrated. The resulting residue was dissolved inAcOEt, washed with water and brine successively, dried with MgSO₄, andconcentrated in-vacuo. The crude product was purified by Combiflasheluting with 40% AcOEt in hexanes.

Step 3

To a solution of 2,2,6,6-tetramethyl-piperidine, (1.18 mL, 0.00700 mol)in tetrahydrofuran (30 mL, 0.4 mol) at −78° C. was added n-butyllithiumin hexane (2.5 M, 3.7 mL). After stirring for 15 min., a suspension ofniacin (0.287 g, 0.00233 mol) in THF was added and the mixture wasstirred at −78° C. for 10 min. The reaction mixture was then warmed to−55° C. for 60 min. A solution of1-{[1-(2,4-dichlorophenyl)cyclopropyl]carbonyl}pyrrolidin-3-one (580 mg,0.0019 mol) in THF (2 mL) was added to the above mixture and stirringwas continued at −55 degrees celsius for 20 min. The reaction mixturewas then allowed to warm to rt for 1 h and then acidified (pH ˜1) using6M HCl aq. solution. The reaction mixture was stirred at rt overnightand then neutralized (pH ˜7). The product from the mixture was extractedwith AcOEt. The organic extract was washed with brine, dried with MgSO₄,and concentrated in-vacuo. The crude product was purified by Combiflashfollowed by separation of the enantiomers using a chiral column. LCMS:m/z 402.0 & 404.0 (M+H)⁺.

Example 5331′-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-4-methoxy-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in steps 1-3 of example 227. LCMS: m/z 399.4 (M+H)⁺.

Example 5341′-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-4-hydroxy-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in steps 1-3 of example 227. LCMS: m/z 385.4 (M+H)⁺.

Example 5356-Chloro-1′-{[1-(3,4-dichlorophenyl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in steps 1-2 of example 232. LCMS: m/z 438.4 (M+H)⁺.

Example 5361′-{[1-(4-Chloro-2-fluorophenyl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined in steps 1-2 of example 95. LCMS: m/z 387.0 (M+H)⁺409.0(M+Na)⁺.

Example 5376-Chloro-1′-{[1-(2,4-difluorophenyl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 232. LCMS: m/z 405.0 (M+H)⁺.

Example 5381′-{[1-(2-Chloro-4-fluorophenyl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 95. LCMS: m/z 387.3 (M+Hr.

Example 5391′-{[1-(2,4-Difluorophenyl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 95. LCMS: m/z 371.1 (M+H)⁺.

Example 5401′-({1-[4-(Methylthio)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 95. LCMS: m/z 381.2 (M+H)⁺ 403.2(M+Na)⁺.

Example 5411′-[(1-{4-[(Trifluoromethyl)thio]phenyl}cyclopropyl)carbonyl]-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 95. LCMS: m/z 435.0 (M+H)⁺ 437.0(M+Na)*.

Example 542(1R)-1′-{[1-(4-Chlorophenyl)cyclopentyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 4. LCMS: m/z 396.5 (M+H)⁺.

Example 543 1-{[1-(4-Chlorophenyl)cyclohexyl]carbonyl}azepane

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 4. LCMS: m/z 320.1 (M+H)⁺.

Example 544 Methyl4-[5-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)pyridin-2-yl]piperazine-1-carboxylate

This compound was prepared by using a procedure analogous to thatoutlined for the synthesis of example 410. LCMS: m/z 477.2 (M+H)⁺.

Example 545N,N-Dimethyl-4-[4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]piperazine-1-carboxamide

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 421. LCMS: m/z 489.3 (M+H)⁺.

Example 546 Methyl4-[3-fluoro-4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]piperazine-1-carboxylate

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 421. LCMS: m/z 494.3 (M+H)⁺.

Example 547(1R)-1′-({1-[2-Fluoro-4-(4-propionylpiperazin-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 421. LCMS: m/z 492.3 (M+H)⁺.

Example 548(1R)-1′-({1-[2-Fluoro-4-(4-isobutyrylpiperazin-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 421. LCMS: m/z 506.2 (M+H)⁺.

Example 549(1R)-1′-[(1-{4-[4-(Cyclopropylcarbonyl)piperazin-1-yl]-2-fluorophenyl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 421. LCMS: m/z 504.2 (M+H)⁺.

Example 550(1R)-1′-({1-[4-(4-Acetylpiperazin-1-yl)-2-fluorophenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 421. LCMS: m/z 478.3 (M+H)⁺.

Example 5514-[3-Fluoro-4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]-N,N-dimethylpiperazine-1-carboxamide

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 421. LCMS: m/z 507.3 (M+H)⁺.

Example 552(1R)-1′-({1-[4-(4-Hydroxypiperidin-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 420. LCMS: m/z 433.2 (M+H)⁺.

Example 553N,N-Dimethyl-1-[4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]piperidine-4-carboxamideStep 1. 1-[(Benzyloxy)carbonyl]piperidine-4-carboxylic acid

Sodium carbonate (1.59 g, 0.0150 mol) was added to a solution ofpiperidine-4-carboxylic acid (0.970 g, 0.00751 mol) in water (15 mL).After the solid was dissolved, benzyl chloroformate (1.54 g, 0.00901mol) was added dropwise. The mixture was stirred at rt for 3 h. Themixture was carefully acidified (pH=4) with 2N HCl, and then wasextracted with DCM (4×10 mL). The combined organic layer was dried overNa2SO4, filtered, and concentrated under reduced pressure to give thedesired product.

Step 2. benzyl 4-[(dimethylamino)carbonyl]piperidine-1-carboxylate

Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(0.442 g, 0.00100 mol) was added to a solution of1-[(benzyloxy)carbonyl]piperidine-4-carboxylic acid (0.263 g, 0.00100mol) in methylene chloride (3.00 mL, 0.0468 mol), followed by4-methylmorpholine (0.440 mL, 0.00400 mol) and dimethylamine intetrahydrofuran (2.00 M, 0.750 mL). The mixture was stirred at rt for 1h and was diluted with ethyl acetate (20 mL). The solution was washedwith NaHCO₃ (7.5%, 3×5 mL) and with brine (5 mL) successively. Theorganic layer was dried over Na₂SO4, filtered, and concentrated underreduced pressure. The residue was purified by Combiflash eluting withethyl acetate/hexane to give the desired product.

Step 3. N,N-dimethylpiperidine-4-carboxamide

Palladium (10.0 mg, 9.40E-6 mol) was added to a solution of benzyl4-[(dimethylamino)carbonyl]piperidine-1-carboxylate (190.0 mg, 0.0006544mol) in methanol (5.0 mL, 0.12 mol) under nitrogen. The mixture washydrogenised with a balloon filled with hydrogen for 3 h. The mixturewas filtered and the filtrate was concentrated to give the desiredproduct.

Step 4.N,N-Dimethyl-1-[4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]piperidine-4-carboxamide

The title compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 420. LCMS: m/z 488.2 (M+H)⁺.

Example 554 Methyl4-[4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]piperidine-1-carboxylate

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 490. LCMS: m/z 475.1 (M+H)⁺.

Example 555 Ethyl4-[4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]piperidine-1-carboxylate

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 490. LCMS: m/z 489.1 (M+H)⁺.

Example 556(1R)-1′-({1-[4-(1-Acetylpiperidin-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 490. LCMS: m/z 459.2 (M+H)*.

Example 557(1R)-1′-({1-[4-(1-Isobutyrylpiperidin-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 492. LCMS: m/z 487.2 (M+H)⁺.

Example 558(1R)-1′-({4-[4-(1-Propionylpiperidin-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 490.

Example 559(1R)-1′-[(1-{4-[1-(3-Methylbutanoyl)piperidin-4-yl]phenyl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 492.

Example 560(1R)-1′-({1-[4-(1-Acetylpiperidin-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 490. LCMS: m/z 460.2 (M+H)⁺.

Example 561(1R)-1′-({1-[4-(1-Isobutyrylpiperidin-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 492. LCMS: m/z 488.2 (M+H)⁺.

Example 562(1R)-1′-({1-[4-(1-Propionylpiperidin-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 492. LCMS: m/z 474.2 (M+H)⁺.

Example 563(1R)-1′-[(1-{4-[1-(3-Methylbutanoyl)piperidin-4-yl]phenyl}cyclopropyl)carbonyl]-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 492. LCMS: m/z 502.2 (M+H)⁺.

Example 564 Methyl4-[4-(1-{[(1R)-3-oxo-1′H,3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]piperidine-1-carboxylate

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 490. LCMS: m/z 476.2 (M+H)⁺.

Example 565 Ethyl4-[4-(1-{[(1R)-3-oxo-1′H,3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]piperidine-1-carboxylate

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 490.

Example 566 Isopropyl4-[4-(1-{[(1R)-3-oxo-1′H,3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]piperidine-1-carboxylate

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 490. LCMS: m/z 504.3 (M+H)⁺.

Example 567 Methyl4-hydroxy-4-[4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]piperidine-1-carboxylate

This compound was prepared by using a procedure analogous to thatdescribed in steps 1-5 of example 210, with the exception that the TFAmediated dehydration in step 4 was omitted. LCMS: m/z 491.2 (M+H)⁺.

Example 568 Ethyl4-hydroxy-4-[4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]piperidine-1-carboxylate

This compound was prepared by using a procedure analogous to thatdescribed in steps 1-5 of example 210, with the exception that the TFAmediated dehydration in step 4 was omitted. LCMS: m/z 505.3 (M+H)*.

Example 569 Methyl4-(5-{1-[(3-pyridin-3-ylpyrrolidin-1-yl)carbonyl]cyclopropyl}pyridin-2-yl)piperazine-1-carboxylate

This compound was prepared by using a procedure analogous to thatdescribed in steps 1-4 of example 163. LCMS: m/z 436.2 (M+H)⁺.

Example 570 Ethyl4-(5-{1-[(3-pyridin-3-ylpyrrolidin-1-yl)carbonyl]cyclopropyl}pyridin-2-yl)piperazine-1-carboxylate

This compound was prepared by using a procedure analogous to thatdescribed in steps 1-4 of example 163.

Example 5711-Acetyl-4-(5-{1-[(3-pyridin-3-ylpyrrolidin-1-yl)carbonyl]cyclopropyl}pyridin-2-yl)piperazine

This compound was prepared by using a procedure analogous to thatdescribed in steps 1-4 of example 163. LCMS: m/z 420.2 (M+H)⁺.

Example 5721-Isobutyryl-4-(5-{1-[(3-pyridin-3-ylpyrrolidin-1-yl)carbonyl]cyclopropyl}pyridin-2-yl)piperazine

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 321. LCMS: m/z 448.3 (M+H)⁺.

Example 5731-(Cyclopropylcarbonyl)-4-(5-{1-[(3-pyridin-3-ylpyrrolidin-1-yl)carbonyl]cyclopropyl}pyridin-2-yl)piperazine

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 321. LCMS: m/z 446.3 (M+H)⁺.

Example 574 Isopropyl4-[4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]piperazine-1-carboxylate

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 421. LCMS: m/z 504.3 (M+H)⁺.

Example 575(1R)-1′-[(1-{4-[6-(Pyrrolidin-1-ylcarbonyl)pyridin-3-yl]phenyl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 250. LCMS: m/z 508.2 (M+H)⁺.

Example 576N-Ethyl-N-methyl-5-[4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]pyridine-2-carboxamide

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 250. LCMS: m/z 496.6 (M+H)⁺.

Example 577N,N-Diethyl-5-[4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]pyridine-2-carboxamide

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 250. LCMS: m/z 510.2 (M+H)⁺.

Example 578 tert-Butyl{4-[5-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)pyridin-2-yl]phenyl}carbamate

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 173. LCMS: m/z 526.2 (M+H)⁺.

Example 579N,N-Dimethyl-1-[5-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)pyridin-2-yl]piperidine-4-carboxamide

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 163, steps 1-3.

Example 580(1R)-1′-{[1-(6-Piperidin-1-ylpyridin-3-yl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 163, steps 1-3. LCMS: m/z 419.2(M+H)⁺.

Example 581(1R)-1′-({1-[2-Fluoro-4-(2-oxopyrrolidin-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 257. LCMS: m/z 435.2 (M+H)⁺;457.1 (M+Na)⁺.

Example 582(1R)-1′-({1-[2-Fluoro-4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 257. LCMS: m/z 438.1 (M+H)⁺.

Example 583(1R)-1′-1′-({1-[4-(2-Oxoazetidin-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 257. LCMS: m/z 403.2 (M+H)⁺.

Example 584(1R)-1′-({1-[2-Fluoro-4-(2-oxoazetidin-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 257. LCMS: m/z 421.1 (M+H)⁺.

Example 5851′-({1-[4-(2-Oxoazetidin-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 257. LCMS: m/z 404.2 (M+H)⁺.

Example 586(1R)-1′-({1-[2-Fluoro-4-(2-oxoazetidin-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 257. LCMS: m/z 422.2 (M+H)⁺.

Example 587 Propyl4-[5-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)pyridin-2-yl]piperazine-1-carboxylate

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 410. LCMS: m/z 505.2 (M+H)⁺.

Example 588 Isobutyl4-[5-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)pyridin-2-yl]piperazine-1-carboxylate

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 410. LCMS: m/z 519.3 (M+H)⁺.

Example 589 Isopropyl4-[5-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)pyridin-2-yl]piperazine-1-carboxylate

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 410. LCMS: m/z 505.3 (M+H)⁺.

Example 590 Ethyl4-[4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]piperazine-1-carboxylate

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 421. LCMS: m/z 490.3 (M+H)⁺.

Example 591 Propyl4-[4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]piperazine-1-carboxylate

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 421. LCMS: m/z 504.3 (M+H)*.

Example 592 Isobutyl4-[4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]piperazine-1-carboxylate

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 421. LCMS: m/z 518.3 (M+H)⁺.

Example 593(1R)-1′-[(1-{4-[4-(Cyclopropylacetyl)piperazin-1-yl]phenyl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed in step 1 of example 421, followed by the BOP mediatedcoupling that was outlined in example 414. LCMS: m/z 500.3 (M+H)⁺.

Example 594(1R)-1′-[(1-{4-[4-(Cyclopropylacetyl)piperazin-1-yl]-2-fluorophenyl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed in step 1 of example 421, followed by the BOP mediatedcoupling that was outlined in example 414. LCMS: m/z 518.2 (M+H)⁺.

Example 595(1R)-1′-[(1-{-4-[4-(3-Methylbutanoyl)piperazin-1-yl]phenyl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure that was analogous tothat described in step 1 of example 421, followed by the BOP mediatedcoupling that was outlined in example 414. LCMS: m/z 502.3 (M+H)⁺.

Example 596(1R)-1′-[(1-{2-Fluoro-4-[4-(3-methylbutanoyl)piperazin-1-yl]phenyl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed in step 1 of example 421, followed by the BOP mediatedcoupling that was outlined in example 414. LCMS: m/z 520.3 (M+H)⁺.

Example 597(1R)-1′-[(1-{4-[4-(Tetrahydro-2H-pyran-4-ylcarbonyl)piperazin-1-yl]phenyl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed in step 1 of example 421, followed by the BOP mediatedcoupling that was outlined in example 414. LCMS: m/z 530.3 (M+H)⁺.

Example 598 Ethyl4-[3-fluoro-4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]piperazine-1-carboxylate

This compound was prepared by using a procedure analogous to thatdescribed in steps 1-2 of example 421. LCMS: m/z 508.3 (M+H)⁺.

Example 599 Propyl4-[3-fluoro-4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]piperazine-1-carboxylate

This compound was prepared by using a procedure analogous to thatdescribed in steps 1 & 2 of example 421. LCMS: m/z 522.3 (M+H)⁺.

Example 6004-[3-Fluoro-4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]-N-methylpiperazine-1-carboxamide

This compound was prepared by using a procedure analogous to thatdescribed in steps 1 & 2 of example 421. LCMS: m/z 493.1 (M+H)⁺.

Example 601(1R)-1′-[(1-{2-Fluoro-4-[4-(3-methylbutanoyl)piperazin-1-yl]phenyl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed in step 1 of example 421, followed by the BOP mediatedcoupling that was outlined in example 414. LCMS: m/z 520.3 (M+H)⁺.

Example 602(1R)-1′-[(1-{4-[4-(Cyclopropylacetyl)piperazin-1-yl]-2-fluorophenyl}cyclopropyl)carbonyl]-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed in step 1 of example 421, followed by the BOP mediatedcoupling that was outlined in example 414. LCMS: m/z 518.2 (M+H)⁺.

Example 603 Methyl4-[3-fluoro-4-(1-{[(1R)-3-oxo-1′H,3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]piperazine-1-carboxylate

This compound was prepared by using a procedure analogous to thatdescribed in steps 1 & 2 of example 421. LCMS: m/z 495.2 (M+H)⁺.

Example 604 Ethyl4-[3-fluoro-4-(1-{[(1R)-3-oxo-1′H,3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]piperazine-1-carboxylate

This compound was prepared by using a procedure analogous to thatdescribed in steps 1 & 2 of example 421. LCMS: m/z 509.2 (M+H)⁺.

Example 605 Propyl4-[3-fluoro-4-(1-{[(1R)-3-oxo-1′H,3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]piperazine-1-carboxylate

This compound was prepared by using a procedure analogous to thatdescribed in steps 1 & 2 of example 421.

Example 606 i-Propyl4-[3-fluoro-4-(1-{[(1R)-3-oxo-1′H,3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]piperazine-1-carboxylate

This compound was prepared by using a procedure analogous to thatdescribed in steps 1 & 2 of example 421.

Example 607 i-Butyl4-[3-fluoro-4-(1-{[(1R)-3-oxo-1′H,3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]piperazine-1-carboxylate

This compound was prepared by using a procedure analogous to thatdescribed in steps 1 & 2 of example 421. LCMS: m/z 537.1 (M+H)⁺.

Example 608(1R)-1′1-[(1-{4-[4-(Cyclopropylcarbonyl)piperazine-1-yl]-2-fluorophenyl}cyclopropyl)carbonyl]-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed in step 1 of example 421, followed by the BOP mediatedcoupling that was outlined in example 414.

Example 609(1R)-1′-[(1-{2-Fluoro-4-[4-(3-methylbutanoyl)piperazin-1-yl]phenyl}cyclopropyl)carbonyl]-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed in step 1 of example 421, followed by the BOP mediatedcoupling that was outlined in example 414. LCMS: m/z 521.3 (M+H)⁺.

Example 610N,N-Dimethyl-5-[4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]pyridine-2-carboxamide

This compound was prepared by using a procedure analogous to thatdescribed in steps 1 & 2 of example 250. LCMS: m/z 482.2 (M+H)⁺.

Example 611N-Ethyl-5-[4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]pyridine-2-carboxamide

This compound was prepared by using a procedure analogous to thatdescribed in steps 1 & 2 of example 250. LCMS: m/z 482.2 (M+H)⁺.

Example 612N-Isopropyl-5-[4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]pyridine-2-carboxamide

This compound was prepared by using a procedure analogous to thatdescribed in steps 1 & 2 of example 250. LCMS: m/z 496.2 (M+H)⁺.

Example 6135-[3-Fluoro-4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]-N-methylpyridine-2-carboxamide

This compound was prepared by using a procedure analogous to thatdescribed in steps 1 & 2 of example 250. LCMS: m/z 486.2 (M+H)⁺.

Example 6145-[3-Fluoro-4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]-N-ethylpyridine-2-carboxamide

This compound was prepared by using a procedure analogous to thatdescribed in steps 1 & 2 of example 250. LCMS: m/z 500.2 (M+H)⁺.

Example 6155-[3-Fluoro-4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]-N-i-propylpyridine-2-carboxamide

This compound was prepared by using a procedure analogous to thatdescribed in steps 1 & 2 of example 250. LCMS: m/z 514.2 (M+H)⁺.

Example 6165-[3-Fluoro-4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]-N,N-dimethylpyridine-2-carboxamide

This compound was prepared by using a procedure analogous to thatdescribed in steps 1 & 2 of example 250. LCMS: m/z 500.2 (M+H)⁺.

Example 6175-[3-Fluoro-4-(1-{[(1R)-3-oxo-1′H,3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]-N-methylpyridine-2-carboxamide

This compound was prepared by using a procedure analogous to thatdescribed in steps 1 & 2 of example 250. LCMS: m/z 487.2 (M+H)⁺.

Example 618N-Ethyl-5-[3-fluoro-4-(1-{[(1R)-3-oxo-1′H,3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]pyridine-2-carboxamide

This compound was prepared by using a procedure analogous to thatdescribed in steps 1 & 2 of example 250. LCMS: m/z 501.2 (M+H)⁺.

Example 6195-[3-Fluoro-4-(1-{[(1R)-3-oxo-1′H,3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]-N-isopropylpyridine-2-carboxamide

This compound was prepared by using a procedure analogous to thatdescribed in steps 1 & 2 of example 250. LCMS: m/z 515.2 (M+H)⁺.

Example 6205-[3-Fluoro-4-(1-{[(1R)-3-oxo-1′H,3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]-N,N-dimethylpyridine-2-carboxamide

This compound was prepared by using a procedure analogous to thatdescribed in steps 1 & 2 of example 250. LCMS: m/z 501.2 (M+H)⁺.

Example 6216-[3-Fluoro-4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]-N-methylnicotinamide

This compound was prepared by using a procedure analogous to thatdescribed in steps 1 & 2 of example 250. LCMS: m/z 486.1 (M+H)⁺.

Example 6226-[3-Fluoro-4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]-N,N-dimethylnicotinamide

This compound was prepared by using a procedure analogous to thatdescribed in steps 1 & 2 of example 250. LCMS: m/z 500.2 (M+H)⁺.

Example 623N-Methyl-6-[4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]nicotinamide

This compound was prepared by using a procedure analogous to thatdescribed in steps 1 & 2 of example 250. LCMS: m/z 468.2 (M+H)⁺.

Example 624N,N-Dimethyl-6-[4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]nicotinamide

This compound was prepared by using a procedure analogous to thatdescribed in steps 1 & 2 of example 250. LCMS: m/z 482.2 (M+H)⁺.

Example 625(1R)-1′-({1-[4-(1-Isobutyryl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure that was analogous tothat described for the synthesis of example 454. LCMS: m/z 485.3 (M+H)⁺.

Example 626(1R)-1′-({1-[4-(1-Propionyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure that was analogous tothat described for the synthesis of example 454. LCMS: m/z 471.3 (M+H)⁺.

Example 627(1R)-1′-({1-[3-Fluoro-4-(3-methyl-1H-pyrazol-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure that was analogous tothat described for the synthesis of example 94. LCMS: m/z 433.1 (M+H)⁺.

Example 628 Methyl4-(4-{1-[(4,4-dimethyl-2-oxo-1-oxa-7-azaspiro[4.4]non-7-yl)carbonyl]cyclopropyl}-3-fluorophenyl)piperazine-1-carboxylateStep 1. tert-butyl3-(1,1-dimethylprop-2-en-1-yl)-3-hydroxypyrrolidine-1-carboxylate

To a suspension of tert-butyl 3-oxopyrrolidine-1-carboxylate (2.40 g,0.0130 mol), 4-bromo-2-methyl-2-butene (3.00 mL, 0.0260 mol) in 15.0 mLsat'd. ammonium chloride and tetrahydrofuran (3.00 mL, 0.0370 mol) wasadded zinc (1.70 g, 0.0260 mol) at rt. Soon after stirring was started,gas and heat were released. After 30 to 45 min., the resulting lightgrey mixture was filtered through celite. The filtration was extractedwith EtOAc. The organic layers were combined, washed with brine, dried(NaSO4) and concentrated in-vacuo. The residue was purified on silicagel, eluting with 0 to 40% EtOAc in hexane, to give the desired product.LCMS (M+Na) 278.2.

Step 2. tert-butyl4,4-dimethyl-2-oxo-1-oxa-7-azaspiro[4.4]nonane-7-carboxylate

To a solution of borane-dimethyl sulfide complex (0.409 mL, 0.00460 mol)in methylene chloride (6.00 mL, 0.0936 mol) was slowly added a solutionof tert-butyl3-(1,1-dimethylprop-2-en-1-yl)-3-hydroxypyrrolidine-1-carboxylate (3.20g, 0.0125 mol) in methylene chloride (6.00 mL, 0.0936 mol) with stirringat rt. After 2 h, the reaction mixture was slowly added to a solution ofchromium(VI) oxide (7.52 g, 0.0752 mol) in acetic acid (45.00 mL, 0.7915mol), and water (5.00 mL, 0.278 mol) at 5° C. After stirring thereaction mixture at rt for 12 h, water (60 mL) and methylene chloride(30 mL) were added. The organic layer was separated and the aqueouslayer was further extracted with methylene chloride (2×30 mL). Theorganic layers were combined, washed with brine (2×30 mL), dried andconcentrated. The residue was purified on silica gel, eluting with 0 to50% EtOAc in hexane, to give the product. LCMS (M+Na) 292.2.

Step 3. 4,4-dimethyl-1-oxa-7-azaspiro[4.4]nonan-2-one hydrochloride

tert-Butyl 4,4-dimethyl-2-oxo-1-oxa-7-azaspiro[4.4]nonane-7-carboxylate(0.20 g, 0.00074 mol) was treated with hydrogen chloride in 1,4-dioxane(4.00 M, 5.00 mL) at rt for 2 h. The volatiles were removed in-vacuo andthe resultant HCl salt was used directly in the next step withoutfurther purification. LCMS (M+H) 170.2.

Step 4. 1-(4-bromo-2-fluorophenyl)cyclopropanecarboxylic acid

This compound was prepared by using a procedure analogous to thatdescribed in step 1 of example 238. NMR analysis confirmed the formationof the desired product, which was used in the next step without furtherpurification.

Step 5. tert-butyl4-(4-{1-[(4,4-dimethyl-2-oxo-1-oxa-7-azaspiro[4.4]non-7-yl)carbonyl]cyclopropyl}-3-fluorophenyl)piperazine-1-carboxylate

To a mixture of 4,4-dimethyl-1-oxa-7-azaspiro[4.4]nonan-2-onehydrochloride (20.3 mg, 0.0000988 mol) and1-{4-[4-(tert-butoxycarbonyl)piperazin-1-yl]-2-fluorophenyl}cyclopropanecarboxylicacid (36.0 mg, 0.0000988 mol) in N,N-dimethylformamide (0.30 mL, 0.0039mol) was added benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (48.1 mg, 0.000109 mol) followed byN,N-diisopropylethylamine (0.0206 mL, 0.000118 mol). After stirring atrt for 1 h, the reaction mixture was quenched with water and extractedwith EtOAc. The organic layers were combined, washed with brine, anddried. The crude residue was used directly in the next step withoutfurther purification. LCMS (M+H) 516.3. (M+Na) 538.3.

Step 6. methyl4-(4-{1-[(4,4-dimethyl-2-oxo-1-oxa-7-azaspiro[4,4]non-7-yl)carbonyl]cyclopropyl}-3-fluorophenyl)piperazine-1-carboxylate

tert-Butyl4-(4-{1-[(4,4-dimethyl-2-oxo-1-oxa-7-azaspiro[4.4]non-7-yl)carbonyl]cyclopropyl}-3-fluorophenyl)piperazine-1-carboxylate(25.0 mg, 0.0000485 mol) was treated with TFA. After stirring at rt for30 min, the volatiles were removed in-vacuo and the residue was dried onhigh vacuum. The resultant TFA salt was dissolved in methylene chloride(0.25 mL, 0.0039 mol) and to this was added triethylamine (0.0203 mL,0.000145 mol) followed by methyl chloroformate (0.00749 mL, 0.0000970mol). The reaction mixture was stirred at rt for 1 h and then thevolatiles were removed in-vacuo. The residue was diluted with methanoland applied directly on RP-HPLC to yield the desired product. LCMS (M+H)474.2.

Example 629 Ethyl4-(4-{1-[(4,4-dimethyl-2-oxo-1-oxa-7-azaspiro[4.4]non-7-yl)carbonyl]cyclopropyl}-3-fluorophenyl)piperazine-1-carboxylate

This compound was prepared by using a procedure analogous to thatdescribed in steps 1-6 of example 628. LCMS: m/z 488.3 (M+H)⁺.

Example 6307-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-4,4-dimethyl-1-oxa-7-azaspiro[4.4]nonan-2-one

This compound was prepared by using a procedure analogous to thatdescribed in steps 1-3 and 5 of example 628. LCMS: m/z 348.2 (M+H)*.

Example 631 Methyl4-(3-fluoro-4-{1-[(3-pyridin-3-ylpyrrolidin-1-yl)carbonyl]cyclopropyl}phenyl)piperazine-1-carboxylate

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 421. LCMS: m/z 4532 (M+H)⁺.

Example 632 Methyl4-(5-{1-[(3-pyridin-3-ylpyrrolidin-1-yl)carbonyl]cyclopropyl}pyridin-2-yl)piperazine-1-carboxylate

This compound was prepared by using a procedure analogous to thatdescribed in steps 1-4 of example 163. LCMS: m/z 436.2 (M+H)⁺.

Example 633 Ethyl4-(5-{1-[(3-pyridin-3-ylpyrrolidin-1-yl)carbonyl]cyclopropyl}pyridin-2-yl)piperazine-1-carboxylate

This compound was prepared by using a procedure analogous to thatdescribed in steps 1-4 of example 163. LCMS: m/z 450.3 (M+H)⁺.

Example 6341-Acetyl-4-(5-{1-[(3-pyridin-3-ylpyrrolidin-1-yl)carbonyl]cyclopropyl}pyridin-2-yl)piperazine

This compound was prepared by using a procedure analogous to thatdescribed in steps 1-4 of example 163. LCMS: m/z 420.2 (M+H)⁺; 442.3(M+Na)⁺.

Example 6351-(3-Methylbutanoyl)-4-(5-{1-[(3-pyridin-3-ylpyrrolidin-1-yl)carbonyl]cyclopropyl}pyridin-2-yl)piperazine

This compound was prepared by using a procedure analogous to thatdescribed in steps 1-4 of example 163.

Example 6361-(Cyclopropylcarbonyl)-4-(5-{1-[(3-pyridin-3-ylpyrrolidin-1-yl)carbonyl]cyclopropyl}pyridin-2-yl)piperazine

This compound was prepared by using a procedure analogous to thatdescribed in steps 1-4 of example 163. LCMS: m/z 446.3 (M+H)⁺; 468.2(M+Na)*.

Example 637 Methyl4-(3-fluoro-4-{1-[(1,3,3-trimethyl-6-azabicyclo[3.2.1]oct-6-yl)carbonyl]cyclopropyl}phenyl)piperazine-1-carboxylate

This compound was prepared by using a procedure that was analogous tothat described for the synthesis of example 421. LCMS: m/z 458.2 (M+H)⁺.

Example 638(1R)-1′-{[1-(6-Azetidin-1-ylpyridin-3-yl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-oneStep 1. 1-(6-chloropyridin-3-yl)cyclopropanecarbonitrile

To a stirred mixture of the (6-chloropyridin-3-yl)acetonitrile (8.00 g,0.0524 mol), benzyltriethylammonium chloride (0.8 g, 0.004 mol), and1-bromo-2-chloro-ethane (8.69 mL, 0.105 mol) was added dropwise sodiumhydroxide, 50% aqueous solution (16.1 mL, 0.419 mol) at 50° C. Afterstirring for 2 h, the reaction mixture was diluted with water and theresulting layers were separated. The aqueous layer was extracted withdichloromethane. The combined organic layers were washed with 1N HCl andbrine successively, dried with magnesium sulfate, filtered, andconcentrated in-vacuo. The crude product was purified by combiflash toobtain 2.5 g of pure product as a white solid.

Step 2. 1-(6-azetidin-1-ylpyridin-3-yl)cyclopropanecarbonitrile

To a solution of 1-(6-chloropyridin-3-yl)cyclopropanecarbonitrile (200.0mg, 0.001120 mol) in 1,4-dioxane (8.00 mL, 0.102 mol) at rt were addedazetidine hydrochloride (128.3 mg, 0.001344 mol), palladium acetate(25.2 mg, 0.000112 mol), and sodium tert-butoxide (288 mg, 0.00291 mol).The reaction mixture was degassed and then microwave irradiated at 150°C. for 40 min. The reaction mixture was quenched with water andextracted with ethyl acetate and dichloromethane. The crude product waspurified by combiflash. LCMS: m/z 200.2 (M+H)⁺.

Step 3. 1-(6-azetidin-1-ylpyridin-3-yl)cyclopropanecarboxylic aciddihydrochloride

Into a microwave vial was transferred1-(6-azetidin-1-ylpyridin-3-yl)cyclopropanecarbonitrile (42.00 mg,0.0002108 mol) and hydrogen chloride (1.00 mL, 0.0326 mol). The mixturewas stirred at 100 degrees for 2 h. Upon completion the crude productwas azeotroped with toluene 3× and used in the next step without furtherpurification.

Step 4. 1-(6-azetidin-1-ylpyridin-3-yl)cyclopropanecarbonyl chloridedihydrochloride

To 1-(6-azetidin-1-ylpyridin-3-yl)cyclopropanecarboxylic aciddihydrochloride (61.00 mg, 0.0002095 mol) were added thionyl chloride(1.00 mL, 0.0137 mol) at 0° C. and the resulting solution was stirred atrt for 1 hr. Upon completion, the reaction mixture was azeotroped withtoluene (3×) and then used in the next step without furtherpurification.

Step 5.(1R)-1′-{[1-(6-azetidin-1-ylpyridin-3-yl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

To a solution of 1-(6-azetidin-1-ylpyridin-3-yl)cyclopropanecarbonylchloride dihydrochloride (64.00 mg, 0.0002067 mol) and(7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonicacid-(1R)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one (1:1)(87.3 mg, 0.000207 mol) in methylene chloride (1.00 mL, 0.0156 mol) wasadded N,N-diisopropylethylamine (0.144 mL, 0.000827 mol) at 0° C. Thereaction mixture was stirred at rt for 1-2 h. Upon completion thereaction mixture was diluted with ethyl acetate and washed with waterand brine successively, dried with sodium sulfate, filtered, andconcentrated. The crude product was purified by prep-LCMS twice toobtain the product as a TFA salt. LCMS: m/z 391.2 (M+H)⁺.

Example 639(1R)-1′-({1-[6-(2-Oxoazetidin-1-yl)pyridin-3-yl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 257. LCMS: m/z 404.2 (M+H)⁺.

Example 640Methyl[3-fluoro-4-(1-{[(1R)-3-oxo-1′H,3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]carbamate

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 257. LCMS: m/z 426.2 (M+H)⁺.

Example 641Methyl[3-fluoro-4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]carbamate

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 257. LCMS: m/z 425.2 (M+H)⁺.

Example 642(1R)-1′-({1-[4-(2-Oxopyrrolidin-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 257. LCMS: m/z 418.2 (M+H)⁺.

Example 643(1R)-1′-[(1-{4-[4-(Cyclopropylcarbonyl)piperazin-1-yl]phenyl}cyclobutyl)carbonyl]-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 163. LCMS: m/z 500.2 (M+H)⁺.

Example 644 Ethyl4-[4-(1-{[(1R)-3-oxo-1′H,3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]piperazine-1-carboxylate

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 163. LCMS: m/z 491.2 (M+H)⁺.

Example 6451-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-3-(1,1-dimethylpropyl)pyrrolidin-3-olStep 1. benzyl3-(1,1-dimethylprop-2-en-1-yl)-3-hydroxypyrrolidine-1-carboxylate

To a suspension of benzyl 3-oxopyrrolidine-1-carboxylate (4.50 g, 0.0205mol) and 4-bromo-2-methyl-2-butene (4.75 mL, 0.0412 mol) in 25.0 mL ofsaturated ammonium chloride and tetrahydrofuran (4.75 mL, 0.0586 mol)was added zinc (2.70 g, 0.0412 mol) at rt. Soon after stirring wasstarted, gas and heat were evolved. After 45 min., the resulting lightgrey mixture was filtered through celite. Layers of the filtrate wereseparated and the aqueous layer of the filtrate was extracted withEtOAc. The organic layers were combined, washed with brine, dried andevaporated in-vacuo. The residue was purified on silica gel, elutingwith 0 to 40% EtOAc in hexane, to give the desired product. LCMS (M+Na)290.2.

Step 2. 3-(1,1-dimethylpropyl)pyrrolidin-3-ol

Benzyl 3-(1,1-dimethylprop-2-en-1-yl)-3-hydroxypyrrolidine-1-carboxylate(56 mg, 0.00019 mol) was dissolved in methanol and to this solution wasadded Pd/C (10% dry, 10 mg). The reaction vessel was purged withhydrogen and allowed to stir for 3 h with a hydrogen balloon. Thecatalyst was filtered off and the filtrate was concentrated in-vacuo toafford the desired product. LCMS (M+H)=158.

Step 3.1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}-3-(1,1-dimethylpropyl)pyrrolidin-3-ol

3-(1,1-Dimethylpropyl)pyrrolidin-3-ol (29.5 mg, 0.000188 mol) wasdissolved in DMF and to this solution were added1-(4-chlorophenyl)cyclopropanecarboxylic acid (44.3 mg, 0.000225 mol),benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(99.6 mg, 0.000225 mol) and N,N-diisopropylethylamine (49 μL, 0.00028mol), and the resulting solution was stirred at rt overnight. Theproduct was purified by prep-HPLC. LCMS (M+H)=336

Example 6467-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}-4,4-dimethyl-1-oxa-7-azaspiro[4.4]nonaneStep 1. tert-butyl3-iodo-4,4-dimethyl-1-oxa-7-azaspiro[4.4]nonane-7-carboxylate

To a solution of tert-butyl3-(1,1-dimethylprop-2-en-1-yl)-3-hydroxypyrrolidine-1-carboxylate (1.00g, 0.00392 mol) in anhydrous acetonitrile (20.00 mL, 0.3829 mol) wereadded sodium bicarbonate (0.658 g, 0.00783 mol) and iodine (2.98 g,0.0117 mol). The resulting mixture was protected from light and stirredat rt for 24 h. The mixture was cooled to 0° C. and sodium thiosulfatewas carefully added until the dark iodine color disappeared. Layers ofthe reaction mixture were separated and the aqueous layer was extractedwith EtOAc. The organic layers were combined, dried and the concentratedin vacuo. The crude ether was purified by CombiFlash, eluting with 0 to30% EtOAc in hexane, to provide the iodo ether as a mixture ofdiastereoisomers. LCMS (M+Na) 404.1.

Step 2. tert-butyl4,4-dimethyl-1-oxa-7-azaspiro[4.4]nonane-7-carboxylate

A mixture of tert-butyl3-iodo-4,4-dimethyl-1-oxa-7-azaspiro[4.4]nonane-7-carboxylate (0.47 g,0.0012 mol), tris(trimethylsilyl)silane (0.456 mL, 0.00148 mol) and2,2′-azo-bis-isobutyronitrile (0.002 g, 0.00001 mol) in toluene (10.00mL, 0.09388 mol) was heated at 90° C. overnight. The volatiles wereremoved in-vacuo and the residue was purified by CombiFlash, elutingwith 0 to 30% EtOAc in hexane, to provide the THF compound. LCMS (M+Na)278.2.

Step 3.7-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}-4,4-dimethyl-1-oxa-7-azaspiro[4.4]nonane

A mixture of tert-butyl2,3,3-trimethyl-1-oxa-6-azaspiro[3.4]octane-6-carboxylate (25.0 mg,0.0000979 mol) and tert-butyl4,4-dimethyl-1-oxa-7-azaspiro[4.4]nonane-7-carboxylate (25.0 mg,0.0000979 mol) was treated with 1 mL of TFA at rt for 30 min. Thevolatiles were removed in-vacuo and the resultant TFA salt was useddirectly in next step. To a mixture of the above made TFA salt inN,N-dimethylformamide (0.50 mL, 0.0064 mol) were added1-(4-chlorophenyl)cyclopropanecarboxylic acid (38.5 mg, 0.000196 mol)and benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (104 mg, 0.000235 mol), followed byN,N-diisopropylethylamine (0.0853 mL, 0.000490 mol). The mixture wasstirred at rt for 2 h and then the product was isolated and purified byRP-HPLC. LCMS (M+H) 334.2.

Example 647 Methyl4-(4-{1-[(3-tert-butyl-3-hydroxypyrrolidin-1-yl)carbonyl]cyclopropyl}-3-fluorophenyl)piperazine-1-carboxylate

This compound was prepared by using a procedure analogous to thatdescribed in steps 1 & 3-6 of example 628. LCMS: m/z 448.1 (M+H)^(+ and)470.1 (M+Na)⁺.

Example 648N,N-Diethyl-5-[3-fluoro-4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]pyridine-2-carboxamide

This compound was prepared by using a procedure analogous to thatdescribed in steps 1 & 2 of example 250. LCMS: m/z 528.2 (M+H)⁺.

Example 649(1S)-1′-({1-[4-(2-Oxopyrrolidin-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 103.

Example 650(1R)-1′-({1-[2-Fluoro-4-(1H-1,2,3-triazol-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 118. LCMS: m/z 419.1 (M+H)⁺.

Example 651(1R)-1′-({1-[2-Fluoro-4-(2H-1,2,3-triazol-2-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 118. LCMS: m/z 419.1 (M+H)⁺.

Example 652(1R)-1′-({1-[2-Fluoro-4-(1H-1,2,4-triazol-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 118. LCMS: m/z 419.1 (M+H)⁺.

Example 653(1R)-1′-({1-[2-Fluoro-4-(4H-1,2,4-triazol-4-yl)phenyl]cyclopropyl}carbonyl)-3H-[2-spirobenzofuran-1,3′-pyrrolidin]-3-one

This compound was prepared by using a procedure analogous to thatdescribed for the synthesis of example 118. LCMS: m/z 419.1 (M+H)⁺.

Example 654N-Ethyl-5-[3-fluoro-4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]pyridine-2-carboxamide

This compound was prepared by using a procedure analogous to thatdescribed in steps 1 & 2 of example 250. LCMS: m/z 500.2 (M+H)⁺.

Example 6555-[3-Fluoro-4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]-N-isopropylpyridine-2-carboxamide

This compound was prepared by using a procedure analogous to thatdescribed in steps 1 & 2 of example 250. LCMS: m/z 514.2 (M+H)⁺.

Example A Enzymatic Assay of 11βHSD1

All in vitro assays were performed with clarified lysates as the sourceof 11βHSD1 activity. HEK-293 transient transfectants expressing anepitope-tagged version of full-length human 11βHSD1 were harvested bycentrifugation. Roughly 2×10⁷ cells were resuspended in 40 mL of lysisbuffer (25 mM Tris-HCl, pH 7.5, 0.1 M NaCl, 1 mM MgCl₂ and 250 mMsucrose) and lysed in a microfluidizer. Lysates were clarified bycentrifugation and the supernatants were aliquoted and frozen.

Inhibition of 11βHSD1 by test compounds was assessed in vitro by aScintillation Proximity Assay (SPA). Dry test compounds were dissolvedat 5 mM in DMSO. These were diluted in DMSO to suitable concentrationsfor the SPA assay. 0.8 μL of 2-fold serial dilutions of compounds weredotted on 384 well plates in DMSO such that 3 logs of compoundconcentration were covered. 20 μL of clarified lysate was added to eachwell. Reactions were initiated by addition of 20 μL ofsubstrate-cofactor mix in assay buffer (25 mM Tris-HCl, pH 7.5, 0.1 MNaCl, 1 mM MgCl₂) to final concentrations of 400 μM NADPH, 25 nM³H-cortisone and 0.007% Triton X-100. Plates were incubated at 37° C.for one hour. Reactions were quenched by addition of 40 μL of anti-mousecoated SPA beads that had been pre-incubated with 10 μM carbenoxoloneand a cortisol-specific monoclonal antibody. Quenched plates wereincubated for a minimum of 30 minutes at RT prior to reading on aTopcount scintillation counter. Controls with no lysate, inhibitedlysate, and with no mAb were run routinely. Roughly 30% of inputcortisone is reduced by 11βHSD1 in the uninhibited reaction under theseconditions.

Test compounds having an IC₅₀ value less than about 20 μM according tothis assay were considered active.

Example B Cell-Based Assays for HSD Activity

Peripheral blood mononuclear cells (PBMCs) were isolated from normalhuman volunteers by Ficoll density centrifugation. Cells were plated at4×10⁵ cells/well in 200 μL of AIM V (Gibco-BRL) media in 96 well plates.The cells were stimulated overnight with 50 ng/ml recombinant human IL-4(R&D Systems). The following morning, 200 nM cortisone (Sigma) was addedin the presence or absence of various concentrations of compound. Thecells were incubated for 48 hours and then supernatants were harvested.Conversion of cortisone to cortisol was determined by a commerciallyavailable ELISA (Assay Design).

Test compounds having an IC₅₀ value less than about 20 μM according tothis assay were considered active.

Example C Cellular Assay to Evaluate MR Antagonism

Assays for MR antagonism were performed essentially as described(Jausons-Loffreda et al. J Biolumin and Chemilumin, 1994, 9: 217-221).Briefly, HEK293/MSR cells (Invitrogen Corp.) were co-transfected withthree plasmids: 1) one designed to express a fusion protein of the GAL4DNA binding domain and the mineralocorticoid receptor ligand bindingdomain, 2) one containing the GAL4 upstream activation sequencepositioned upstream of a firefly luciferase reporter gene (pFR-LUC,Stratagene, Inc.), and 3) one containing the Renilla luciferase reportergene cloned downstream of a thymidine kinase promoter (Promega).Transfections were performed using the FuGENE6 reagent (Roche).Transfected cells were ready for use in subsequent assays 24 hourspost-transfection.

In order to evaluate a compound's ability to antagonize the MR, testcompounds are diluted in cell culture medium (E-MEM, 10%charcoal-stripped FBS, 2 mM L-glutamine) supplemented with 1 nMaldosterone and applied to the transfected cells for 16-18 hours. Afterthe incubation of the cells with the test compound and aldosterone, theactivity of firefly luciferase (indicative of MR agonism by aldosterone)and Renilla luciferase (normalization control) were determined using theDual-Glo Luciferase Assay System (Promega). Antagonism of themineralocorticoid receptor was determined by monitoring the ability of atest compound to attenuate the aldosterone-induced firefly luciferaseactivity.

Compounds having an IC₅₀ of 100 μM or less were considered active.

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including all patent,patent applications, and publications, cited in the present applicationis incorporated herein by reference in its entirety.

1. A compound which isN-methyl-5-[4-(1-{[3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]pyridine-2-carboxamide,or a pharmaceutically acceptable salt thereof.
 2. A compound which isN-methyl-5-[4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]pyridine-2-carboxamide,or a pharmaceutically acceptable salt thereof.
 3. A compound which isN-methyl-5-[4-(1-{[(1R)-3-oxo-1′H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]pyridine-2-carboxamide.4. A pharmaceutical composition comprising a compound according to claim1, or a pharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable carrier.
 5. A method of treating a diseasein a patient, wherein the disease is selected from obesity, diabetes,glucose intolerance, insulin resistance, hyperglycemia, hyperlipidemia,glaucoma, hypertension, osteoporosis inflammation, renal disease,atherosclerosis, arteriosclerosis, coronary artery disease, thrombosis,angina, vascular wall damage, stroke, dyslipidemia,hyperlipoproteinemia, diabetic dyslipidemia, mixed dyslipidemia,hypercholesterolemia, hypertriglyceridemia, metabolic syndrome orgeneral aldosterone-related target organ damage, the method comprisingadministering to said patient a therapeutically effective amount of acompound of claim 1, or a pharmaceutically acceptable salt thereof.
 6. Amethod of treating Type II diabetes in a patient comprisingadministering to said patient a therapeutically effective amount of acompound of claim 1, or a pharmaceutically acceptable salt thereof.
 7. Apharmaceutical composition comprising a compound according to claim 2,or a pharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable carrier.
 8. A pharmaceutical compositioncomprising a compound according to claim 3 and at least onepharmaceutically acceptable carrier.
 9. A method according to claim 5,wherein the disease is obesity.
 10. A method according to claim 5,wherein the disease is diabetes.
 11. A method according to claim 5,wherein the disease is glucose intolerance.
 12. A method according toclaim 5, wherein the disease is insulin resistance.
 13. A methodaccording to claim 5, wherein the disease is hyperglycemia.
 14. A methodaccording to claim 5, wherein the disease is hypertension.
 15. A methodaccording to claim 5, wherein the disease is hyperlipidemia.
 16. Amethod of treating a disease in a patient, wherein the disease isselected from obesity, diabetes, glucose intolerance, insulinresistance, hyperglycemia, hyperlipidemia, glaucoma, hypertension,osteoporosis inflammation, renal disease, atherosclerosis,arteriosclerosis, coronary artery disease, thrombosis, angina, vascularwall damage, stroke, dyslipidemia, hyperlipoproteinemia, diabeticdyslipidemia, mixed dyslipidemia, hypercholesterolemia,hypertriglyceridemia, metabolic syndrome or general aldosterone-relatedtarget organ damage, wherein the method comprises administering to saidpatient a therapeutically effective amount of a compound of claim 2, ora pharmaceutically acceptable salt thereof.
 17. A method of treatingtype II diabetes in a patient comprising administering to said patient atherapeutically effective amount of a compound of claim 2, or apharmaceutically acceptable salt thereof.
 18. A method according toclaim 16, wherein the disease is obesity.
 19. A method according toclaim 16, wherein the disease is diabetes.
 20. A method according toclaim 16, wherein the disease is glucose intolerance.
 21. A methodaccording to claim 16, wherein the disease is insulin resistance.
 22. Amethod according to claim 16, wherein the disease is hyperglycemia. 23.A method according to claim 16, wherein the disease is hypertension. 24.A method according to claim 16, wherein the disease is hyperlipidemia.